RuizJ ClinMicrobiolRev201932e00007-1

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Transferable Mechanisms of Quinolone Resistance from 1998 Onward
Article in Clinical Microbiology Reviews · August 2019

DOI: 10.1128/CMR.00007-19
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REVIEW
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Transferable Mechanisms of Quinolone Resistance from 1998

Onward
Joaquim Ruiza
a
Universidad Continental, Lima, Peru
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Utility of quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Evolution of Quinolone Resistance over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Quinolone Resistance Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
GENERAL OVERVIEW OF TMQR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Nomenclature of the Transferable Mechanisms of Quinolone Resistance . . . . . . . . . . . . . . . . 9
Is it correct to use the term plasmid-mediated quinolone resistance? . . . . . . . . . . . . . . . . 10
TMQR misidentification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Changing Resistance Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Clinical Relevance of TMQR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Molecular Epidemiology of TMQR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Qnr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Qnr Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Qnr Families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
QnrA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
QnrB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
QnrC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
QnrD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
QnrE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
QnrS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
QnrVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Chromosomal Qnr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Qnr Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Original Qnr Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Mechanisms of Qnr Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
In vitro mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
QUINOLONE MODIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AAC(6=)Ib-cr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AAC(6=)Ib-cr subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Other Quinolone Modification Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
TRANSFERABLE EFFLUX PUMPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
OqxAB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
QepA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
QacA and QacB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Other Transferable Efflux Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
TMQR AND THE FUTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
AUTHOR BIO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Citation Ruiz J. 2019. Transferable mechanisms

of quinolone resistance from 1998 onward. Clin
Microbiol Rev 32:e00007-19. https://doi.org/10
SUMMARY While the description of resistance to quinolones is almost as old as .1128/CMR.00007-19.
these antimicrobial agents themselves, transferable mechanisms of quinolone resis- Copyright © 2019 American Society for
Microbiology. All Rights Reserved.
tance (TMQR) remained absent from the scenario for more than 36 years, appearing
Address correspondence to
first as sporadic events and afterward as epidemics. In 1998, the first TMQR was joruiz.trabajo@gmail.com.
soundly described, that is, QnrA. The presence of QnrA was almost anecdotal for Published 14 August 2019
years, but in the middle of the first decade of the 21st century, there was an explo-
October 2019 Volume 32 Issue 4 e00007-19 Clinical Microbiology Reviews cmr.asm.org 1

Ruiz Clinical Microbiology Reviews
sion of TMQR descriptions, which definitively changed the epidemiology of quino-

lone resistance. Currently, 3 different clinically relevant mechanisms of quinolone re-
sistance are encoded within mobile elements: (i) target protection, which is
mediated by 7 different families of Qnr (QnrA, QnrB, QnrC, QnrD, QnrE, QnrS, and
QnrVC), which overall account for more than 100 recognized alleles; (ii) antibiotic ef-
flux, which is mediated by 2 main transferable efflux pumps (QepA and OqxAB),
which together account for more than 30 alleles, and a series of other efflux pumps
(e.g., QacBIII), which at present have been sporadically described; and (iii) antibiotic
modification, which is mediated by the enzymes AAC(6=)Ib-cr, from which different
alleles have been claimed, as well as CrpP, a newly described phosphorylase.
KEYWORDS CrpP, OqxAB, PMQR, QepA, quinolones, TMQR, aac(6)Ib-cr, antibiotic
resistance, plasmid-mediated quinolone resistance, qnr
INTRODUCTION
Research on transferable mechanisms of quinolone resistance (TMQR) (see “Is it correct
to use the term plasmid-mediated quinolone resistance?” below, for an explanation
about the use of this term and acronym) is almost as old as quinolones themselves
(1–3). Nonetheless, despite some sporadic unconfirmed descriptions of TMQR (2–6) and
the presence of transferable mechanisms of resistance related to a slowdown of the
bacterial duplication time associated with a 2.2-kb region of the plasmid pKM101
containing the korB, traL, korA, and traM genes (7), TMQR remained undetected. In most
of the early studies in which quinolone resistance transfer was claimed, transconjugants
were selected with nalidixic acid, which possesses a relatively high frequency of
mutation (8, 9). Furthermore, some studies used low MICs to select nalidixic acid-
resistant transconjugants as nalidixic acid resistant (e.g., 8 ␮g/ml in a study by Jonsson
[2]). These findings suggest that the selection of spontaneous mutants rather than the
presence of true transconjugants is the most feasible scenario. This led to a debate
about the feasibility of TMQR development (10, 11). Indeed, some studies on TMQR
were further reanalyzed, and it was proposed that plasmids act as a mutator factor able
to induce the development of nalidixic acid resistance (12), and the presence of
spontaneous quinolone target mutations (10) showed a lack of transfer of nalidixic acid
resistance (13).
Thus, for 36 years after the first nalidixic acid description (14), TMQR remained a
unicorn or a vanishing hitchhiker, a myth or urban legend, until 1998, when the
presence of TMQR was first unequivocally demonstrated (15).
Quinolones
Quinolones are synthetic products that were first synthetized in 1949 (16). There-
after, a high number of derivatives and related substances were developed, some of
which showed antibacterial properties. Although some quinolone derivative molecules
were patented in the late 1950s, it is largely considered that the quinolone era began
in 1962, with the synthesis of nalidixic acid (14, 17–19). The first clinical trial reports on
the use of nalidixic acid are from 1963 (20–23). Subsequently, nalidixic acid was
introduced into clinical practice as early as 1964 (18, 24, 25) albeit limited to the
treatment of urinary tract infections (26). Despite this limitation, this agent has played
a role in the treatment of other infections, such as those of the gastrointestinal tract,
especially in some developing areas (27–30). In subsequent years, the quinolone family
grew, and some of its members were introduced into the antibacterial clinical arma-
mentarium; these include oxolinic acid (31), piromidic acid (32), cinoxacin (33), and
pipemidic acid (34), among others. Although first proposed in 1960 (17), the next step
in the history of quinolones was the addition of a fluorine atom, which opened the door
to the fluoroquinolone era. Norfloxacin is considered the starting point of this era (35),
despite the fluorine atom first being present in another quinolone introduced into
clinical practice, flumequine (36). This fluorine atom was thereafter maintained in
almost all the quinolones introduced into clinical practice, largely expanding their
October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 2

Transferable Mechanisms of Quinolone Resistance Clinical Microbiology Reviews
bacterial spectra and levels of activity (37). Nonetheless, some recent quinolones, a few
of which were introduced into clinical practice only a few years ago (e.g., garenoxacin,
nemonoxacin, and ozenoxacin), lack the fluorine atom substituent at position 6,
although they may present a fluorine atom(s) in other positions (for instance, the
garenoxacin molecule possesses an OCHF2 group in position 8), usually referred to as
“desfluoroquinolones” or “nonfluorinated quinolones” (38–42). Finally, some recently
developed molecules present antibiotic hybrid characteristics, such as cadazolid, a
quinoxolidinone (fluoroquinolone-oxazolidone hybrid molecule) that has been inves-
tigated to treat Clostridium difficile infections (43) (Fig. 1).
In summary, since the beginning of the quinolone era, more than 10,000 quinolones
have been synthetized, and their activities and properties have been explored (25, 44,
45), with more than 40 being approved for either human or veterinary applications.
Currently, 21 quinolones remain in human use in the European Union and/or the
United States (Fig. 2), while several others are used in other countries; for instance,
balofloxacin has been approved for human use in South Korea and India (46, 47).
Despite the fact that the classification of quinolones, or other antibacterial agents,
in “generations” is imprecise and subject to different interpretations, the quinolones
have traditionally been classified into 4 generations based on their spectrum of activity
(48, 49) (see Table 1 for definitions used in this article). In addition, the quinolone ring
may be subdivided into 4 subclasses (cinnolines, naphthyridines, pyridopyrimidines,
and quinolines) related to the position of the nitrogen atoms within the molecule. Of
these, the quinoline subclass has by far the largest number of quinolones that have
been introduced into clinical/veterinary practice. Furthermore, other structurally related
molecules, such as 2-pyridones, quinazoline-2,4-diones, and isothiazoloquinolones, also
have antibacterial activity. Of these, 2-pyridones have probably been the most exten-
sively studied. Although usually classified as a different antibiotic family, the
2-pyridones might be structurally considered a fifth quinolone subclass. In fact, they
differ from quinolones only in the position of the N atom, which is located at the ring
juncture, and the subsequent loss of a double bond (50) (Table 1 and Fig. 3). Never-
theless, to date, no 2-pyridone has been introduced into clinical practice.
Utility of quinolones. Quinolones have been used to treat a great variety of
bacterial infections by either Gram-positive or Gram-negative microorganisms, includ-
ing intracellular pathogens (37, 51–56). Quinolones have also been used or proposed
for prophylactic treatment of specific at-risk populations, such as patients with cirrhosis
or neoplasms, and in posttransplant or presurgery/postsurgery patients (57–62). None-
theless, in several cases, the benefits have been controversial or unsatisfactory, and the
addition of new factors, such as increasing levels of antibiotic resistance, has led to the
restriction or avoidance of some of these uses (60, 63–65).
The utility of quinolones has also been explored in the treatment of parasitic
infections such as malaria, toxoplasmosis, and leishmaniosis; fungal infections (e.g.,
Candida albicans or Aspergillus fumigatus); or viral infections such as those by BK
polyomavirus, rhinovirus, and hepatitis C virus (HCV) (66–75). Meanwhile, the structur-
ally related quinolone molecules elvitegravir and ivacaftor are currently in use as an
integrase inhibitor in HIV therapy and in the treatment of cystic fibrosis, respectively
(76–78). Moreover, in addition to the antineoplastic potential of some established
quinolones such as gemifloxacin (79), new quinolone derivatives are being explored as
specific antineoplastic agents (71, 80).
Beyond human uses, fluoroquinolones have also been included in the veterinary
armamentarium, in livestock as a growth promoter (an application which is currently
forbidden in different countries, including those of the European Union) (81–83), and as a
prophylactic agent (84, 85) or in the treatment of infections (81, 85). Indeed, at the end of
the 20th century, quinolones ranked among the antibiotics most widely used worldwide,
with ciprofloxacin being considered the antibacterial agent most frequently used (81).
Adverse events. To our knowledge, adverse events were described in early clinical
trials of nalidixic acid (20, 21), and the first warning as to the possible occurrence of
adverse events related to the use of quinolones was reported as far back as 1965 (4).

FIG 1 The chronology of the quinolones (1949 to the present). The top side of the temporal line indicates the years of discovery/synthesis of a
series of representative quinolones. In all cases, the year of the most ancient report found in the literature is reported. Note that although several
thousand quinolones have been synthetized and their anti-infective potential has been explored, only a selection is presented. Furthermore, no
quinolone without a “specific” name has been included (because in the vast majority of cases, their development was discontinued), leading to
a lower number of quinolones from ⬃2010 onward, as most are in the first stages of development (for instance, DS-8587 or KPI-10 [both of which
are described in articles from 2013 {452, 453}]). The bottom side of the temporal line indicates a series of milestones in the history of quinolones.
1, fluoroquinolone-oxazolidone hybrid molecule (43).

FIG 2 Quinolones in use in human therapeutics in the United States and the European Union. In gray are
quinolones currently (as of March 2019) used in human health. In orange are quinolones that have been
discontinued (marked only when this information has been found). In yellow are quinolones proposed
for withdrawal from use on March 2019 (https://www.ema.europa.eu/en/documents/referral/quinolone
-fluoroquinolone-article-31-referral-annex-i_en.pdf). Note that discontinuation may be related to adverse
events (e.g., trovafloxacin) or to economical and market reasons. Some of these antibiotics (or other
quinolones that have not been approved or are in the investigational phase) may be considered in
special circumstances as last-resort treatment (454). Note that in all the cases, the data listed refer only
to the United States and the European Union (including the United Kingdom at the time of writing). The
introduction or current or past use/nonuse of these or other quinolones in other geographical areas may
not be inferred by this figure. a, extracted from https://www.accessdata.fda.gov/scripts/cder/ob/index
.cfm; b, in use in at least one European Union member country (including the United Kingdom at the time
of writing) (https://www.ema.europa.eu/documents/referral/quinolone-fluoroquinolone-article-31
-referral-annex-i_en.pdf). G, generation; Desf, desfluoroquinolone.
Since then, several adverse effects related to the use of quinolones have been de-
scribed, including blood disorders, central nervous system events (dizziness, sleep
disorders, and seizures, among others), gastrointestinal disturbances and C. difficile-
associated diarrhea, myasthenia gravis exacerbations, peripheral neuropathy, photo-
toxicity, rashes, and torsade de pointes, among others (25, 45, 86, 87). Of note, adverse
events are related to specific quinolone substituents. Thus, halogen atoms at position
8, such as a chloro atom in clinafloxacin or sitafloxacin or a fluor atom in sparfloxacin,
have been involved in phototoxicity reactions (45, 88–90). Interestingly, several adverse
events have been related to ethnic background (89). In this sense, ethnic differences in
phototoxicity reactions have led to the introduction of sitafloxacin into human clinical
practice in several Asian countries, such as Japan (https://www.pmda.go.jp/files/
000152974.pdf) and Thailand (91), while remaining absent from the antibiotic arma-
mentariums of the European Union, the United States, and other countries.

TABLE 1 General classification of the main quinolonesa

Quinolonesb
Fluoroquinolones
Structural class 1st generation 2nd generation 3rd generation 4th generation Desfluoroquinolones
Naphthyridines Nalidixic acid (V) Enoxacin Ecenofloxacin Gemifloxacin
Esafloxacin Tosufloxacin Trovafloxacin
Oxoenoxacin Zabofloxacin
Cinnolines Cinoxacin
Pyridopyrimidines Piromidic acid

Pipemidic acid
Quinolines Droxacin Amifloxacin Balofloxacin Antofloxacin Nemonoxacin

Flumequine (V)c Benofloxacin (V) Cetefloxacin Avarofloxacin Ozenoxacin
Metioxated Ciprofloxacin (V) Chinfloxacin Besifloxacine Garenoxacin
Miloxacin Enrofloxacin (V) Difloxacin (V) Caderofloxacin Piroxacin
Oxolinic acid (V) Fandofloxacin Danofloxacin (V) Clinafloxacin
Rosoxacin Fleroxacin Grepafloxacine Delafloxacin
Tioxacin Lomefloxacin Ibafloxacin (V) Finafloxacin
Merafloxacin Levofloxacinf Gatifloxacin
Nadifloxacin Marbofloxacin (V) Lascufloxacin
Norfloxacin (V) Orbifloxacin (V) Levonadifloxacinf
Ofloxacin (V) Olamufloxacin Moxifloxacin
Pefloxacin Pazufloxacin Premafloxacin
Pirfloxacin Pradofloxacin (V) Prulifloxacin
Rufloxacin Sarafloxacin (V) Sitafloxacine
Sparfloxacin
Temafloxacine
2-Pyridonesg
aV, frequent use (past or present) for animal health (livestock and/or companion animals). Note that the list of quinolones used in veterinary health include
quinolones with extended use for human health, such as ciprofloxacin, norfloxacin, and ofloxacin, some of which are included in the list of essential medicines
(http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017_FINAL_amendedAug2017.pdf?ua⫽1). Most of the listed quinolones have not been in-
troduced into either human or veterinary medicine. Note that some quinolones may be found in the literature under different names. For instance, avarofloxacin,
benofloxacin, caderofloxacin, enoxacin, nadifloxacin, pirfloxacin, rosoxacin, and tioxic acid may also be found as acorafloxacin, vebufloxacin, cadrofloxacin, enofloxa-
cin, jinofloxacin, irloxacin, acrosoxacin, and tioxacin, respectively.
bNote that in some classifications, several quinolones may be considered to belong to another generation. The criteria followed in the present scheme are as follows.
First generation indicates quinolones presenting activity against some Gram-negative microorganisms (e.g., not against P. aeruginosa), almost all of which are
nonfluorinated and with a limited spectrum of clinical indications. Second generation indicates quinolones with an expanded spectrum of activity (includes most
Gram-negative microorganisms, e.g., P. aeruginosa, and some Gram-positive organisms), with expanded indications (which may include systemic infections), and
marked with the stable introduction of a fluor atom in position 6. Third generation is similar to second generation, with expanded Gram-positive coverage; members of this
class may possess activity against some atypical pathogens. Fourth generation is similar to third generation but with activity against anaerobic microorganisms.
Desfluoroquinolones are new quinolones in which the fluor atom in position 6 has been removed, usually not included in the fourth-generation scheme.
cCarries a fluor atom in position 6.
dMetioxate has almost the same structure as tioxic acid but with COOH in position 3 modified by the presence of 4-methylpiperidine (https://pubchem.ncbi.nlm.nih
.gov/search/#query⫽Metioxate). Nonetheless, it is usually classified as a first-generation quinolone.

ePresence of a chloride substituent in position 8.
fThose with the prefix “levo” (i.e., levofloxacin and levonadifloxacin) are isomers of previously described quinolones which exhibit enhanced activity.
gAt present, no 2-pyridone has been introduced as an antibacterial agent in clinical practice. Examples of this antibacterial agent group are ABT-719 (50) and KRQ-
10018 (459). The 2-pyridone ABT-719 should not be confused with modimelanotide, which also receives the same ABT-719 code. Modimelanotide is an unrelated
molecule developed later and designed to prevent acute kidney injury (460).
The most commonly known adverse events are considered to be antibiotic class related
and include arthralgias, cartilage affectations, tendinitis, and tendon ruptures. Due to
known teratogenic and mutagenic effects, the use of quinolones has classically been
avoided in pregnant women and children (88, 92). It is of note that different reports have
reanalyzed the use of quinolones in children, including neonates, and they have been
considered to be safe and beneficial in specific circumstances, such as severe or life-
threating infections by quinolone-susceptible microorganisms; furthermore, secondary ef-
fects were considered reversible (88, 93–96). In this line, several fluoroquinolones have been
introduced in established pediatric antibacterial armamentariums, such as tosufloxacin in
Japan for treating respiratory infections (97, 98). Meanwhile, a recent meta-analysis and
systematic review on the use of quinolones in pregnant women highlighted the safety of
using fluoroquinolones during the first trimester of pregnancy (99).

FIG 3 General structure and subclasses of quinolones. Quinolones have a bicyclic structure. At present,
4 quinolone subclasses, differing in the positions and numbers of the nitrogen atoms present in the basal
bicyclic structure, have been developed and introduced into clinical and/or veterinary settings (A to D).
In these 4 quinolone subclasses, the atom numeration is usually described using the quinoline subclass
as a general model (A). Position 1 is considered the N atom, and the subsequent positions are numbered
anticlockwise. Note that no atoms present in the ring junctions are numbered. Fluoroquinolones present
a fluoridine as a substituent in position 6. The radicals present in positions 1 and 7 are critical for
quinolone-target interactions. Thus, it has been proposed that radical 1 interacts with amino acid 83 of
GyrA (numeration of E. coli) or its equivalent in ParC by means of Van der Waals forces, while radical 7
interacts with amino acid 87 by charge attraction (455). (A) Quinoline. This molecule presents a nitrogen
atom only in position 1 (e.g., oxolinic acid, ciprofloxacin, and norfloxacin). (B) Cinnoline. This molecule
presents nitrogen atoms in positions 1 and 2 (e.g., cinoxacin). (C) Pyridopyrimidine. The molecule
presents nitrogen atoms in positions 1, 6, and 8 (e.g., pipemidic acid). (D) Naphthyridine. This molecule
presents nitrogen atoms in positions 1 and 8 (e.g., nalidixic acid and trovafloxacin). (E) 2-Pyridone. This
molecule is usually not considered a member of the quinolone antibiotic family. The atom numeration
of this molecule differs from those in panels A to D (the nitrogen atom in the upper ring juncture is
numbered as atom 5).
There have been recent warnings regarding the possible development of aortic
aneurysms and dissection in patients at risk as antibiotic-class-related severe adverse
events (100, 101). In this line, mice challenged with a high-fat diet and a low-dose
angiotensin infusion exposed to ciprofloxacin were more prone to developing aortic
destruction and aneurysms (102). Other unexpected severe adverse events are shown
in Table 2.
Immediate quinolone-induced hypersensitivity, mediated by quinolone-specific IgE
(103), has been on the rise in the last years, with quinolones currently likely ranking
second to ␤-lactams as the antimicrobial agents most frequently involved in allergic
reactions (104), with an especially high incidence among patients treated with moxi-
floxacin (105–107). The severity of these reactions ranges from anaphylaxis and urticaria
to life-threatening anaphylactic shock (87, 105), with a few fatal cases being reported
in the literature (108).
Evolution of Quinolone Resistance over Time

Although early studies described the presence of nalidixic acid-resistant clinical
isolates, highlighting the feasibility of selecting nalidixic acid resistance during treat-
ment (20, 21, 109), up until the 1980s, reports of quinolone resistance were unusual (1,
2, 4, 110–112). In the 1990s, descriptions of quinolone-resistant microorganisms rapidly
increased (111, 113–119), in parallel with the exponential growth of quinolone use (120,
121). In fact, at the end of the 20th century in specific geographical areas, some

TABLE 2 Quinolone-related severe adverse eventsa

Severe adverse event(s)b Relevant quinolone(s)c
Aortic destruction and aneurysmsd FQd
Cardiovascular events GRX, MXF, SPX
Dysglycemia CIP, CLX, GAT, LVX
Hemolysis and HUS TMX
Hepatotoxicity TMX, TVA
Nephritis TSX
Phototoxicity CLX, FLE, LOM, PFX, SPX, STX
Renal failure TMX
Thrombocytopenia SPX, TMX, TSX
aCIP, ciprofloxacin; CLX, clinafloxacin; FLE, fleroxacin; FQ, fluoroquinolones; GAT, gatifloxacin; GRX,
grepafloxacin; LOM, lomefloxacin; LVX, levofloxacin; MXF, moxifloxacin; PFX, pefloxacin; SPX, sparfloxacin;
STX, sitafloxacin; TMX, temafloxacin; TSX, tosufloxacin; TVA, trovafloxacin; HUS, hemolytic-uremic syndrome.
bThis is a nonexhaustive list. Only especially severe adverse events are shown, which in several cases have
resulted in patient death (45, 87, 88, 90, 101, 461). In several cases, these findings have led to the
discontinuation of research, withdrawal from clinical practice, and strong restrictions to specific nonsystemic
applications (such as topical or ophthalmic), to serious life- or limb-threatening infections, or to last-resort
applications, such as compassionate use of several of these quinolones (45, 100, 454, 462, 463). Note that
these regulations may differ among different countries. In addition, ethnic background may play a role in
the frequency of these adverse events (89). For information about systemic quinolones in use in the
European Union and the United States, see Fig. 2.
cMost relevant quinolones involved in the specific adverse event. Note that other quinolones may also be
able to cause similar effects in specific cases or circumstances.

dMost of the cases are related to ciprofloxacin treatment but proposed to be an antibiotic class effect (100,
101).
microorganisms, such as Campylobacter spp., presented extremely high percentages of

fluoroquinolone resistance, which in some cases were ⬎80% (111, 122), and therapeu-
tic failure and/or the development of resistance during quinolone treatment was
increasingly reported (123–127).
The risks of the rising levels of antimicrobial resistance worldwide have been
increasingly discussed and highlighted (128–130), with subsequent proposals for the
implementation of different actions (128, 131, 132). Nevertheless, in the present
century, the continuously rising global trend toward the isolation of pathogenic or
nonpathogenic quinolone-resistant microorganisms has remained unaltered (55, 113,
133–140) and has expanded to regions with limited access to antibiotic agents (141–
143). In fact, the use of quinolones has been compromised in different areas because
of the high percentages of quinolone resistance among specific pathogens (134,
144–147).
Quinolone Resistance Mechanisms

The first studies determining the molecular mechanisms involved in the develop-
ment of quinolone resistance showed the important role of point mutations in the
genes encoding the different topoisomerase type II subunits (GyrA and GyrB for DNA
gyrase and ParC and ParE for topoisomerase IV). In addition, the role of increased efflux
activity or permeability alterations, both resulting in decreased cytoplasm quinolone
concentrations, was also observed (37) although frequently misconsidered (148). Other
less frequent chromosomal mechanisms of quinolone resistance have been described,
such as an increase in resistance levels related to lower expression levels of GrlA/GrlB
(ParC/ParE) (149).
Although classically not considered mechanisms of resistance, bacteria may also
display life strategies that make it difficult for quinolones to access their targets and
thereby allow microorganisms to survive in the presence of quinolones. The best
example of this is the development of biofilms, in which the extracellular matrix
diminishes the interaction of quinolones with microorganisms (150, 151). Microorgan-
isms can also use quiescence as a way to survive in the presence of quinolones (151),
probably because these agents need the presence of biological processes involving the
activity of topoisomerases to be active. In this line, a curious phenomenon of paradox-
ical bacterial survival has been described in the presence of extremely high levels of

quinolones, which modify the bactericidal action of quinolones to a bacteriostatic

effect. It has been proposed that this is related to the blocking of bacterial processes
leading to a quiescent state (152).
As mentioned above, the search for TMQR was unfruitful for years, until 1998, when
Martínez-Martínez et al. (15) described an increase in quinolone resistance related to
the presence of an unknown determinant present in a Klebsiella pneumoniae plasmid
which was related to the presence of a Qnr determinant (see QNR, below). Thereafter,
AAC(6=)Ib-cr, a variant of an aminoglycoside acetylase able to modify some quinolones,
was described in 2006 (153). Until recently, this enzyme remained the only quinolone-
inactivating enzyme, but in 2018, a Pseudomonas aeruginosa phosphorylase, called
CrpP, was first described (154). Finally, in 2003, a transferable mechanism able to confer
olaquindox resistance to Escherichia coli (155) was first detected, being characterized as
a resistance-nodulation-division (RND) efflux system and called OqxAB (156). Its ability
to extrude some quinolones was established in 2007 (157), almost in parallel with the
description of QepA (158, 159), another transferable efflux pump. Further studies have
led to the description of other transferable efflux pumps able to confer resistance to
quinolones (see Transferable Efflux Pumps, below).
GENERAL OVERVIEW OF TMQR

Classically, the relevance of TMQR of Gram-negative and Gram-positive microorgan-
isms is not equivalent (160). Despite the description of the exchange of genes between
Gram-negative and Gram-positive microorganisms (161, 162) and the spread of anti-
biotic resistance determinants among them (161–165), prior to 2016, only a few specific
Gram-positive TMQR, such as QacBIII, had been detected in Staphylococcus aureus (166).
Nonetheless, PCR studies performed in the last years have shown the presence of other
TMQR, such as qnrA, qnrB, qnrD, oqxAB, or aac(6=)Ib-cr, in Gram-positive microorganisms
(167–169). Unfortunately, to our knowledge, of these genes, only oqxA and oqxB have
been fully validated by DNA sequencing (169).
Nomenclature of the Transferable Mechanisms of Quinolone Resistance

The term “qnr” was successfully introduced in the first article in the field to refer to
the first plasmid-mediated mechanism of quinolone resistance described (15). Although
the meaning of “qnr” was not explicitly explained in the text (15), it has been largely
considered an acronym of “quinolone resistance.” Similarly, although not abbreviated,
Martínez-Martínez et al. (15) also used the term “plasmid-mediated quinolone resis-
tance,” which was adopted in most subsequent works in the field, although to the best
of my knowledge, the commonly used acronym “PMQR” was introduced in 2006, after
the description of AAC(6=)Ib-cr (170). Further chromosomal descriptions of transferable
qnr or other transferable genes involved in quinolone resistance have led to proposal
of other genetic nomenclatures (see “Is it correct to use the term plasmid-mediated
quinolone resistance?,” below).
The introduction of a letter to define the exact qnr gene was first introduced in 2005,
when a new Qnr exhibiting only 59% amino acid identity with the only known Qnr at
that time (currently QnrA1) was detected in Shigella flexneri 2b in Japan; this new Qnr
was named “QnrS” because of the microorganisms from which it was recovered (171).
Thereafter, the qnr gene, which was first isolated in 1998, was rapidly reported as qnrA
to avoid confusion (172–174). Although qnrA2 was described in 2004 (GenBank acces-
sion number AY675584), the introduction of allele numeration was also developed in
2005, with the reporting of a series of different qnrA gene variants (171).
The subsequent names QnrB, QnrC, and QnrD were adopted in alphabetical order
for gene name assignation. Meanwhile, QnrVC maintains the first name proposed,
related to its presence in Vibrio cholerae (175). Regarding QnrE, the last transferable Qnr
family described (in 2017), both the alphabetical order and the original bacterial source
(Enterobacter spp.) coincided at the moment to propose a specific name (176).
Regarding transferable efflux pumps, the term OqxAB was proposed in 2004 be-
cause the first description of this transferable efflux pump was made during a study

aimed at determining the presence of olaquindox resistance mechanisms (155, 156).

Similar to other TMQR, allelic numeration was proposed after the description of amino
acid variants in both OqxA and OqxB (177).
Later, in 2007, another efflux pump able to extrude quinolones was isolated and
named “qepA” for “quinolone efflux pump” (158, 159). Nonetheless, in the related
GenBank submission (GenBank accession number EF150886), Périchon et al. (159) used
the unsuccessful term “pef” (derived from “plasmid efflux pump”) to refer to this
mechanism of resistance. Then, in 2008, after the description of a new qepA gene
differing in 2 amino acid positions, a number was introduced to refer to qepA variants
differing in one or a few amino acid residues (178, 179).
The term “qac” was established in the 1980s to refer to a series of Gram-positive
efflux pumps able to extrude quaternary ammonium compounds (180), and it is used
in the nomenclature of efflux pumps belonging to different families, such as the RND
(e.g., QacA and QacB) and small multidrug resistance (SMR) (e.g., QacG, QacH, and QacJ)
families (181). Similar to what is described for Qnr, different letters differentiate
different genes (e.g., qacA and qacB, etc.). Despite being analyzed in multiple studies,
the role of qac determinants in resistance to quinolones has been established only
recently; in the same study, roman numerals were introduced to differentiate QacB
alleles (166).
Regarding inactivating enzymes, the term AAC(6=)Ib-cr was derived from the no-
menclature of aminoglycoside-modified enzymes, because this gene derives from that
encoding the aminoglycoside acetyltransferase AAC(6=)Ib (for an explanation of the
meaning of the term, see the revision of Ramírez and Tolmasky [182]); the “cr” at the
end represents “ciprofloxacin resistance” (153). Finally, CrpP, the most recently de-
scribed TMQR, was named as such for ciprofloxacin resistance protein, plasmid encoded
(154).
Is it correct to use the term plasmid-mediated quinolone resistance? Classically,
mobilizable genes leading to the development of quinolone resistance have been
collectively named PMQR genes in order to highlight their nonchromosomal nature (15,
170). Nonetheless, plasmids may exchange material with other chromosomal or plas-
midic elements, and therefore, the plasmid content may be fully or partially integrated
within the bacterial chromosome (183, 184). The integration of mobilizable antibiotic
resistance genes within the bacterial chromosome has been largely described. Thus,
many transferable resistance genes, including those encoding ␤-lactamases, amino-
glycoside-modifying enzymes, or trimethoprim resistance determinants, have been
detected in the chromosomes of different microorganisms (141, 185–196). With regard
to TMQR, this finding has also been described. Thus, the aac(6=)Ib-cr gene (197, 198) and
the qepA1 gene (e.g., GenBank accession number NZ_CP019051) have been described
in the chromosome of E. coli, while oqxAB, indigenous to Klebsiella spp. (160, 199–201),
has been detected in the chromosome of Salmonella enterica serovar Derby (202).
Similarly, different transferable qnr determinants, such as qnrA, qnrB, qnrS, and qnrVC,
have been found to be inserted within the chromosomes of nonindigenous microor-
ganisms, such as E. coli, Acinetobacter baumannii, and Pseudomonas putida (195,
203–206).
Therefore, the term PMQR may not be completely correct and might lead to a
misunderstanding and erroneous interpretations of the genetic locations of the quin-
olone resistance determinants. In this sense, some authors have introduced alternative
nomenclatures to refer to these genes, such as quinolone resistance determinants
(QRDs), quinolone resistance genes (QRGs), transferable mechanisms of quinolone
Resistance (TMQR), or transferable quinolone resistance determinants (TQRDs) (160,
196, 207, 208). The acronym TMQR is used throughout this review.
TMQR misidentification. Unfortunately, misidentification of genes is a relevant
scientific problem and involves all study fields. This problem can lead to erroneous
result interpretation, and when stated in the literature or in gene sequence databases,
a series of bona fide misanalyzed or subsequent erroneously interpreted data is
generated. In this sense, GenBank is a powerful tool in which millions of DNA sequences

are deposited. However, this database may have misidentified or erroneous sequences,
which compromises the utility of the tool (209).
Regarding TMQR, the clearest example of misidentification is related to the expo-
nential growth which qnr scientific literature has undergone in the last years. This
phenomenon has favored the publication of partial qnr sequences to which allele
numeration has been “assigned” or, more seriously, full qnr sequences which have been
erroneously assigned to either an allele or a qnr family (209, 210). The possibility of
posting sequences in GenBank without validation (see “Qnr Classification,” below), in
order to be verified and correctly named and numbered, contributes to the perpetu-
ation and amplification of nomenclature errors because they are included in the most
relevant gene database worldwide (209, 210). Indeed, upon analyzing 1,657 Qnr
sequences recorded in GenBank (209), it was observed that 340 (20.5%) sequences
presented a major error. These errors included 105 Qnr sequences introduced in
GenBank as “PipB2,” a type III effector protein which has been associated with the
formation of vesicles (211); 145 sequences classified within an erroneous Qnr family; 16
sequences with an erroneous allele assignation; 24 partial sequences with an allele
assignation; and 50 sequences with a nonnormative initial ATG codon assigned (209).
Moreover, 449 (27.1%) of the sequences were only partially or not identified, and 9
unreported transferable alleles were detected, which were later allele numbered within
GenBank records (209). Another finding is the nondetection of qnr genes when
sequences are submitted to GenBank, leading to “hidden” qnr genes which can be
detected only after a direct DNA BLAST search (210). This may lead to unnoticed
mistakes in the discussion of results obtained in field studies.
Although this problem is less frequent because of the lower number of variants, it
also affects the remaining TMQR. Thus, different qepA variants are recorded in GenBank
as “qac” variants, while a series of GenBank-recorded qepA variants remain undescribed
(see “QepA,” below) (179). Regarding OqxAB, it is of note that a series of allelic variants
of OqxA and OqxB, which are either transferable or indigenous to K. pneumoniae, have
received further numeration; for instance, “OqxB20” and “OqxB29” were first reported
in the same article (212).
In an effort to minimize these problems, GenBank has developed “RefSeq” to name
proteins as consistently and as correctly as possible (for instance, a search for qnrA
alleles may be performed at https://www.ncbi.nlm.nih.gov/pathogens/isolates#/ref-
gene/gene_family:qnrA; for other determinants, all that is needed is a change from
“qnrA” to the desired gene). Nonetheless, it is the responsibility of all researchers to
facilitate this effort, providing the most correct and normative nomenclature, submit-
ting newly described sequences to the respective repositories, when available, in order
to be numbered in a rational manner, and providing these data in GenBank submis-
sions, manuscripts, and presentations.
The most serious problem with AAC(6=)Ib-cr is the assertion of new allelic variants
in the development of quinolone resistance. Since a single amino acid change may alter
the functionality of an antibiotic-modifying enzyme by amplifying, limiting, or modi-
fying its spectrum of activity, it is important to determine the effect of any new allele
on different quinolones prior to asserting its role as a quinolone resistance determinant.
Changing Resistance Paradigms

There are reports of exceptional microorganisms, such as Stenotrophomonas malto-
philia, in which chromosomal target mutations have no relevance in the acquisition of
nalidixic acid or fluoroquinolone resistance. In these microorganisms, quinolone resis-
tance is mainly related to highly potent efflux pumps acting concomitantly with factors
such as the presence of native chromosomal Qnr (213–216). Nonetheless, efflux pump
overexpression by itself does not normally lead to full resistance to quinolones.
Therefore, the presence of target mutations has even been reported to be the most
relevant quinolone resistance mechanism in both Gram-positive and Gram-negative
microorganisms (37). In the latter microorganisms, it has been established that the
activity of old quinolones, such as nalidixic acid, is highly affected by these mutations,

with the resistance breakpoint being surpassed in the presence of a single target
mutation (37, 217–219). Thus, the bacterial phenotype of resistance to nalidixic acid and
susceptibility (or diminished susceptibility) to fluoroquinolones has frequently been
described and associated with the presence of at least one target mutation (37, 115,
118, 119, 217, 218), being considered a risk factor for the development of full resistance
to fluoroquinolones (219, 220). These findings have led to the modification of several
CLSI quinolone resistance breakpoints in 2016 (221, 222). In fact, in several reports, the
use of nalidixic acid was suggested as a predictor of fluoroquinolone resistance (219,
223). Along this line, natural resistance to nalidixic acid and at least diminished
susceptibility to fluoroquinolones related to the presence of a specific wild-type GyrA
amino acid in position 83 and/or position 87 (E. coli numeration) have been described
in microorganisms such as Bartonella spp. and Brevundimonas spp., among others
(224–226).
The eruption of TMQR has altered this scenario, increasing the isolation of
quinolone-resistant microorganisms in the absence of target mutations and descrip-
tions of microorganisms exhibiting the unusual phenotype of nalidixic acid suscepti-
bility and ciprofloxacin resistance. Thus, the presence of more than one TMQR may
increase the final MIC for resistance breakpoints even in the absence of quinolone
target mutations (153, 227–231, 471). Furthermore, this finding has also been reported
in isolates in which only one TMQR was identified or introduced (15, 228, 231–233). For
instance, a recent swine isolate of Salmonella enterica serovar Rissen, without target
mutations and in which the only TMQR detected was QnrVC4, showed MICs of nalidixic
acid, norfloxacin, and ciprofloxacin of 32 ␮g/ml, 1 ␮g/ml, and 0.5 ␮g/ml, respectively
(231). In this line, it has been shown that the levels of quinolone resistance produced
by QnrB and QnrS are directly related to their levels of expression. Thus, it was observed
that the final MICs of ciprofloxacin were increased when QnrB1, QnrS1, or derived
mutants with impaired functionality were cloned in expression vectors under IPTG
(isopropyl-␤-D-thiogalactopyranoside) induction (234, 235). Furthermore, a study by
Garoff et al. (236) in which qnrB and qnrS (no allele was specified) were cloned alone
into E. coli (strain MG1655) and expressed under the control of different promoters
showed that the MIC of ciprofloxacin increased according to gene expression levels
until reaching plateaus of 0.375 and 1 ␮g/ml for qnrB and qnrS, respectively, repre-
senting increases of 25 and 66.6 times the original MIC for MG1655 (0.015 ␮g/ml) (Fig.
4). Although in this study, qnrB and qnrS were cloned as a single resistance determinant,
it is important to again highlight that the final MICs are the result of multiple
phenomena, therefore also being related to intrinsic bacterial factors such as cell wall
permeability or intrinsic efflux pump activity. In microorganisms such as Acinetobacter
spp. or P. aeruginosa, low membrane permeability and the extrusion of quinolones by
several powerful efflux pumps strongly affect the intrinsic MICs of quinolones. Thus,
intrinsic ciprofloxacin resistance ranges from 0.125 to 1 ␮g/ml (⬎8 times that of E. coli
MG1655) to 0.25 to 4 ␮g/ml (⬎16 times that of E. coli MG1655) in the cases of A.
baumannii and P. aeruginosa, respectively (37, 237–239). Thus, it could be predicted
that similar qnrB or qnrS expression levels in these microorganisms lead to the detec-
tion of higher final MICs.
Prior to the boom of TMQR, another atypical scenario was the presence of the
unusual phenotype of nalidixic acid susceptibility and ciprofloxacin (fluoroquinolone)
resistance or diminished susceptibility. Previously, this had been reported only in
specific microorganisms such as the above-mentioned S. maltophilia, in which this
phenotype is especially frequent, probably due to the unusual mechanisms involving
the development of quinolone resistance (214, 216). In addition, this phenotype is also
shown in a few E. coli clinical isolates, with decreased quinolone uptake associated with
the highly unusual GyrA mutation D82G (240, 241) and in in vitro-constructed E. coli
mutants carrying the GyrA substitution G81D (242). This has also been observed in
Campylobacter jejuni and Neisseria gonorrhoeae, for which no analysis of the mecha-
nisms of resistance has been reported (117, 243), or in C. jejuni presenting the GyrA
substitution T86A, thereby suggesting the presence of an unidentified factor (244).

FIG 4 Effect of expression levels of qnrS and qnrB on final MICs. In both panels, the mRNA levels are
relative to those of the control genes hcaT, idnT, and cysG and are expressed in log10 units (based on data
from reference 236). (A) qnrS; (B) qnrB.
Nonetheless, this phenotype may be mediated by the concomitant presence of TMQR

that have an effect on specific quinolones, such as AAC(6=)Ib-cr or the QepA-like efflux
pumps, affecting ciprofloxacin activity but being unable to affect that of nalidixic acid
(160). Furthermore, the concomitant presence of any of these TMQR with others
affecting all quinolone MICs even at different levels, such as Qnr determinants, also
leads to the same scenario (133, 245). In this way, in 2012, two K. pneumoniae isolates
without DNA gyrase or topoisomerase IV amino acid substitutions but carrying the
aac(6=)-Ib-cr, qnrB4, and qnrS2 genes and showing resistance to ciprofloxacin but
susceptibility to nalidixic acid were described (245). Similarly, the transfer of aac(6=)Ib-cr
and qnrS1 from a clinical isolate of Salmonella enterica serovar Typhimurium to a
competent E. coli isolate resulted in a transconjugant exhibiting an MIC of ciprofloxacin
of 2 ␮g/ml (133).
Clinical Relevance of TMQR

As mentioned above, the levels of resistance conferred by TMQR are low and usually
do not surpass the established quinolone resistance breakpoints. Therefore, while it
might be considered that TMQR play an accessory and secondary role in the develop-
ment of quinolone resistance, several factors should be taken into account (Table 3).
Thus, the effect of TMQR on final MICs is always additive to that conferred by other
transferable or chromosome-encoded mechanisms of quinolone resistance (160); ex-
pression levels may modulate the effect of TMQR on the final MIC (236), and no factor
limits the number of identical or different TMQR that may be present in a single
microorganism, encoded or not within the same genetic structure (138, 197, 229,
245–254) (Tables 3 and 4); for instance, 3 copies of the qnrB6 gene, 2 copies of the
aac(6=)Ib-cr gene, and 1 qnrB pseudogene are carried on the E. coli plasmid pAMSH1
(GenBank accession number CP030940) (Table 4). In the same sense, Vinué et al. (229)
described an E. coli isolate carrying the aac(6=)Ib-cr, qnrA1, qepA1, and oqxAB genes.
Similarly, a recent study showed the presence of up to 5 qnrA1 copies within a plasmid
selected under ciprofloxacin pressure (251).

TABLE 3 Essential data on TMQR

Datum
Epidemiologya
Usually encoded and spread together with other antibiotic resistance determinantsb
Possible presence of more than one TMQR in the same genetic structure or microorganisms
Horizontal dissemination of transposons, genomic islands, phages
Vertical dissemination (indigenous presence, integration within chromosome)
Effect on quinolone MIC

Additive effect ¡ possibility of full resistance to FQ
Multiple copies, 1 expression ¡ 1MIC
In some cases, a maximum MIC can be reached, irrespective of TMQR expression levels
Affects all quinolones (Qnr)
Affects specific quinolones [AAC(6=)Ib-cr, CrpP, QepA, OqxAB, other efflux pumps]
Single amino acid substitutions, 1 or 2 final MICs or modify substrate profile
Facilitation of acquisition of further mutations leading to increasing levels of quinolone
resistance
No effect on increasing no. of quinolone target mutations
Possible effect on MICs of unrelated agents (e.g., novobiocin, tigecycline, or colistin)
aThe effect on clinical outcome is a negative impact (pending confirmation).
bThis finding results in coselection of antibiotic resistance.
Furthermore, the presence of decreased susceptibility to quinolones has also been

shown to be a risk factor for the development of full quinolone resistance (219). In this
sense, early studies showed a scenario in which the presence of qnr genes increased by
⬎100 times the selection of quinolone-resistant mutants in the absence of a general
mutator effect (15). Nonetheless, a study published in 2019 showed that qnrB has a
general mutator effect in both the presence and the absence of ciprofloxacin and also
showed that QnrB interacts with DnaA, subsequently regulating the formation of the
DnaA-oriC complex and leading to the upregulation of genes near oriC. This results in
DNA replication stress, which in turn favors both an increase in the number of plasmids,
independently of Qnr-topoisomerase interactions, and higher mutation rates (255). In
the last years, the effect of TMQR on the further selection of quinolone resistance
mechanisms and bacterial survival in the presence of lethal concentrations of quino-
lones has been analyzed (256–258). Indeed, Cesaro et al. showed that the selection of
quinolone-resistant microorganisms does not differ in the presence or absence of
qnrA1, qnrA3, qnrB1, or qnrS1 determinants and that the presence of these qnr deter-
minants increases quinolone mutant prevention concentrations (MPCs). They also
highlighted an unexpected finding in which the presence of qnr determinants results
in a significantly (P ⬍ 0.0001) lower number of quinolone target mutations (256). Thus,
in the genetic environment of E. coli J53 and KL16, while 65/329 (20%) of the mutants
selected in the presence of qnr carried at least 1 gyrA mutation, the number of gyrA
mutations increased up to 94/119 (79%) among the mutants selected from qnr-free E.
coli (256). Similar studies with qnrA1 by Goto et al. showed increases in the MPC and a
lack of association with the selection of target mutations (257). Furthermore, upon
extending this scenario to other TMQR, such as qepA and aac(6=)Ib-cr (258), it was
suggested that the presence of TMQR favors the selection of a series of chromosomal
mutations outside the classical quinolone targets that are able to act in an additive or
cooperative manner, each providing lower levels of resistance but concomitantly
achieving high levels of quinolone resistance (258). In this sense, Vinué et al. (258)
showed that under quinolone pressure, the presence of qnrA favors the overexpression
of different efflux pumps such as AcrAB-TolC, AcrEF-TolC, MdtEF, and MdtK (also known
as YdhE), which, in most cases, correlates with the presence of mutations in different
regulator genes like marR, soxR, and evgA. Furthermore, most of these mutants also
presented decreased expression of the porins OmpC and OmpF as well as a series of
mutations in apparently unrelated genes whose possible role in the development of
low levels of quinolone resistance remains to be elucidated (258). In addition, a series
of mutations in genes involved in the inner part of the core oligosaccharide of

TABLE 4 Epidemiology of coresistance involving TMQRa
Antibiotic resistance determinantsb
Reference(s) or GenBank
GSc Inc type Size (kb) TMQR Other [AMG/␤-lactam (␤L/ESBL/CBP/pAmpC)/CHL/CST/FOF/MC/RIF/SUL/TET/TMP/other] accession no.
pHS1387 48 aac(6=)Ib-crd aadA16/(—/—/—/—)/—/—/—/—/arr3/sul1⌬/—/dfrA27/— 464, 465
pC1865 220 aac(6=)Ib-cr aadA2/(blaTEM-1, blaOXA1e/blaCTX-M-15/—/—)/—/—/—/—/—/sul1/—/dfrA12/— 197
pA3T HI2 253 aac(6=)Ib-cr, oqxAB aph(4)-Ia/(blaOXA-1/blaCTX-M-14/—/—)/catB3, floR/—/fosA3/—/arr3/sul1, sul2/—/dfrA12/— 254
pD90-1 222.5 aac(6=)Ib-cr, oqxAB aac(3)-IV, aadA5, armA, strA, strB/(blaTEM-1b, blaOXA-1/blaCTX-M-6/—/—)/catB3, floR/—/fosA3/—/arr3/sul1, sul2/—/dfrA17/— 252
pHSH2 68 aac(6=)Ib-cr, qnrA1f —/(blaOXA-1/—/—/—)/catB3/—/—/—/arr3/sul1/—/—/—/— 253
pHE96 70 aac(6=)Ib-cr, qnrA3g aadA16⌬/(blaOXA-1/—/—/—)/catB3e/—/—/—/arr3/sul1/—/dfrA27⌬/— 246
pNDM-MAR H 267 aac(6=)Ib-cr, qnrB1 —/(blaOXA-1/blaCTX-M-15/blaNDM-1/—)/cat, catB3/—/—/—/—/—/—/—/— 250
ND aac(6=)Ib-cr, qnrB4h —/(blaOXA-1/—/—/blaDHA-1)/catB3/—/—/—/arr3/sul1/—/—/— 245
pC2367 R 195 aac(6=)Ib-cr, qnrB6i aadA16/(—/—/—/—)/—/—/—/—/arr3/sul1/—/dfrA27/— 197
pAMSH1j 257.4 aac(6=)Ib-cr, qnrB6, qnrB⌬ aac(3)IId, aph(3=)Ib, aph(6)Id/(blaTEM-1/blaCTX-M-55/—/—)/floR/—/—/mph(A)/arr3/sul1, sul2/tet(A)/dfrA27/— CP030940
October 2019 Volume 32 Issue 4 e00007-19

ND aac(6=)Ib-cr, qnrB10k —/(blaOXA-1/—/—/—)/catB3/—/—/—/arr3/sul1/—/—/— 248
Transferable Mechanisms of Quinolone Resistance
p19051-IMP HI5 316.8 aac(6=)Ib-cr,l qnrB52, qnrS1 aacC2, aadA2, armA, strA, strB/(blaTEM-1B/blaCTX-M-3, blaSHV-12/blaIMP-4/—)/—/—/fosA3/mph(E), msr(E)/arr3/sul1/—/dfrA12/tmrBm 247
pUM505 I 123 crpP —/(—/—/—/—)/—/—/—/—/—/—/—/—/— 154
pHNSHP45-2 H12 251.5 oqxAB aac(3)-IV, aadA1, aadA2, aph(3=)-Ia/(—/blaCTX-M-14/—/—)/cmlA, floR/mcr-1/fosA3/—/—/sul1, sul2, sul3/—/dfrA12/— 278
pOLA52 X1 52 oqxAB —/(blaTEM-1/—/—/—)/—/—/—/—/—/—/—/—/— 200
pHPA FII 70 qepA1 rmtB/(blaTEM-1/blaCTX-M-12/—/—)/—/—/—/mph(A)/—/—/—/—/— 158
pIP1206 FI 168 qepA1 aadA4, rmtB/(blaTEM-1/—/—/—)/catA1/—/—/—/—/—/tet(A)/dfrA17/— 286
pMG252n 185.6 qnrA1 aadA2, aadB, aph(3)II/(blaCARB-2/—/—/blaFOX-5)/catB3, catB11, cmlA1, mdtL/—/—/mph(E), msr(E)/—/sul1/—/—/dfrA19 15, 251, 284, 317
SGI-1Vo 42.9 qnrA1 aac(6=)Ib, aadB/(—/blaVEB-6/—/—)/—/—/—/—/—/sul1/tet(A)⌬/dfrA1/— 277
pJIBE401p L/M ⬎150 qnrB2 aac(6=)Ib4/(—/—/blaIMP-4, blaOXA-73/—)/catB3c/—/—/mph(A)/—/sul1/—/—/— 279
pENVA H 253 qnrB4 aacC2, aadA/(blaTEM-1/blaCTX-M-15/—/blaDHA-1)/—/—/—/—/—/sul1/tet(A)/dfrA15/— 276
pECY6-7 ColE 2.7 qnrB19 —/(—/—/—/—)/—/—/—/—/—/—/—/—/— 466
pLRM24 80 qnrB19 aac(6=)Ib, aadA1/(blaTEM-1/—/blaKPC-3/—)/—/—/—/—/—/—/—/—/— 283
Chromq qnrB62 aac(6=)II/(—/—/blaVIM-2/—)/—/—/—/—/—/sul1/—/— 275
pHS10 120 qnrC —/(—/—/—/—)/—/—/—/—/—/—/—/—/— 340
p2007057 4.27 qnrD1 —/(—/—/—/—)/—/—/—/—/—/—/—/—/— 344
pKP41M M1 70 qnrE1 aac(6=)-Ib, aadA1/(blaTEM-1, blaOXA-9/blaCTX-M-8/—/—)/—/—/—/—/—/—/—/—/— 273
pGN26-KPC X6 46.3 qnrS1 —/(blaTEM-1⌬/—/blaKPC-2/—)/—/—/—/—/—/—/—/—/— 280
pK245 98 qnrS1 aacC2, strA, strB/(blaLAP-2/blaSHV-2/—/—)/cat2/—/—/—/—/—/tet(D)/dfrA14/— 272
(Continued on next page)
cmr.asm.org 15
Clinical Microbiology Reviews
TABLE 4 (Continued) Ruiz
Antibiotic resistance determinantsb

Reference(s) or GenBank
GSc Inc type Size (kb) TMQR Other [AMG/␤-lactam (␤L/ESBL/CBP/pAmpC)/CHL/CST/FOF/MC/RIF/SUL/TET/TMP/other] accession no.
pUR19829-KPC21 Q2 12.7 qnrS2 —/(—/—/blaKPC-21/—)/—/—/—/—/—/—/—/—/— 281
pKAZ3 A/C 148 qnrVC1 —/(—/blaVEB-9/—/—)/—/—/—/—/—/—/tet(A)=, tet(C)/dfrA1, dfrA23/— 274
pKAZ4r A/C 167 qnrVC1 aadA1e (blaOXA-10/blaSHV-12/—/—)/—/—/—/—/arr3/sul1/—/—/— 274
pVAS3-1 A/C 175 qnrVC4 aac(6=)I, aadA1, aadA2, aph(3=)I, strA, strB/(blaOXA-10/—/—/blaCMY-2)/cmlA1, cmlA5, floR/—/—/mph(A)/—/—/tet(A)/dfrA14/— 285
aTMQR are shown in alphabetical order and thereafter by allelic variant. Prior or posterior presence in the table does not preclude a prior or posterior identification or a specific position within the reported genetic structure. For the
exact gene position within the structure, see the references provided. In all cases, the final effect of the genes reported should be considered within the bacterial genetic background. Furthermore, the presence of additional
mutations in the chromosome or other genes involved in antibiotic resistance cannot be ruled out. When the TMQR are carried within an integron environment, information about the full integron gene content is reported. GS,
genetic structure; Inc type, plasmid incompatibility group; TMQR, transferable mechanisms of quinolone resistance; AMG, aminoglycosides; ␤L, ␤-lactam (not including third- or fourth-generation cephalosporins, carbapenems, or
monobactams); ESBL, extended-spectrum ␤-lactamases; CBP, carbapenems; pAmpC, plasmid AmpC; CHL, chloramphenicol; MB, monobactams; MC, macrolides; RIF, rifampin and derivatives; SUL, sulfonamides; TET, tetracyclines;
TMP, trimethoprim; Δ, pseudogene (presence of an internal stop codon or deletion leading to a frameshift) with an impaired ability to confer antibiotic resistance (in these cases, the gene is reported for epidemiological purposes);
ND, not determined; 3=-CS, 3= conserved segment.

bOnly antibiotic resistance genes in the reported structure and therefore spreading concomitantly. Note that the presence of a specific antibiotic resistance-encoding gene is not synonymous with phenotypic resistance; the effect
(e.g., TMQR) may be only a modest increase in MICs, not reaching the established resistance breakpoint, or gene expression may be downregulated or impaired. Furthermore, in several cases, such as specific TMQR,
aminoglycoside-modifying enzymes, or transferable mechanisms of macrolide resistance, the resistance conferred by the reported mechanisms may not be extended to all antibiotic class family members. The number of described
genetic structures carrying TMQR alone or in association with other antibiotic resistance genes is enormous and growing on an almost daily basis. Only a series of representative genetic structures are described here. When a TMQR
is reported to be present within a plasmid but no exact plasmid name is provided, the name of the bacterial strain is used as the plasmid name, and the genetic structure name is highlighted in boldface type.
cIn several cases, the whole sequence or full content data of the reported genetic structure are not available, with the subsequent possible presence of unnoticed antibiotic resistance genes; for instance, although not
reported when fully sequenced (GenBank accession number MK638972), in the plasmid pMG252, which started the TMQR era, 2 other ␤-lactamases with isoelectric points of 7.0 and 7.6 were detected, in addition to ␤-
lactamases with isoelectric points of 5.6 and 7.2, and further identified as blaCARB-2 and blaFOX-5 and reported in the table (15).
daac(6=)Ib-cr is harbored within an ⬃4.8-kb integron {In1021 [aac(6=)Ib-cr-arr3-dfrA27-aadA16-IS15-sul1Δ-IS1]}.
eAlso reported as bla

OXA-30 or blaOXA-1/30.
OXA-1-catB3-arr3 qacE⌬1-sul1-ISCR1-qnrA1-ampR-qacE⌬1-sul1]}.
fBoth TMQR are harbored within an ⬃15-kb complex class 1 integron {In37 [aac(6=)Ib-cr-bla
gThe qnrA3 gene is located after a structure (qacE⌬1-sul1-ISCR1-qnrA3) suggesting the presence of an undescribed complex class 1 integron, while aac(6=)Ib-cr is placed upstream of qnrA3 just after the location of IS26 and
tnpA within In640 [aac(6=)Ib-cr-blaOXA-1-arr3-dfrA27⌬-aadA16⌬-qacE⌬1].

hIntegron identical to In37 but carrying a qnrB4 allele instead of qnrA1 and an additional bla
DHA-1 gene just upstream from the qnrB gene.
iIntegron similar to In1021 but with a different 3=-CS region leading to a complex class 1 integron. A qnrB6 gene is located in the additional variable region [aac(6=)Ib-cr-arr3-dfrA27-aadA16-qacE⌬1-sul1-ISCR1-qnrB6-qacE⌬1 sul1].
jThe aac(6=)Ib-cr and qnrB6 genes are harbored within a complex integron {In1229-like [aac(6=)Ib-cr-arr3-dfrA27-qacE⌬1-sul1-ISCR1-ORF (putative oxidoreductase)-qnrB6-pspF⌬-qacE⌬1-sul1]}. This integron is present twice in
the plasmid. An additional qnrB6 gene within a structure resembling that of the end of the complex integron is also present.
kIntegron identical to In37 but carrying a qnrB10 allele instead of qnrA1.
lThe aac(6=)Ib-cr gene is harbored within a class 1 integron {In1231 [aac(6=)Ib-cr-arr3]}.
mTmrB confers resistance to tunicamycin, an antibiotic produced by members of the genus Streptomyces (e.g., Streptomyces lysosuperificus) which targets the cell wall synthesis of Gram-positive bacteria. Toxicity for
eukaryotic cells has precluded its clinical use (467).

nqnrA1 is harbored within a complex class 1 integron (In580-like [bla
CARB-2-aadA2-cmlA1c-catB11-qacE⌬1-sul1-ISCR1-qnrA1-qacE⌬1-sul1-ISCR1-dfrA19]). Of note, in the original article, pMG252 was reported to have a size of
⬃56 kb (15).
oGenomic island.
pThe TMQR is present within a complex class 1 integron environment {In585-like [bla
IMP-4-qacG2-aac(6=)Ib4-catB3-qacE⌬1-ISCR1-sapA-orf2-qnrB2-pspF-qacE⌬1-sul1]}.
qThe TMQR is present within a complex class 1 integron environment {In1184 [bla
VIM-2-aac(6=)II-gucD-qacE⌬1-sul1-ISCR1-pspF-qnrB62-qacE⌬1-sul1]}.
rThe qnrVC1 gene is harbored in a class 1 integron (In1214 [arr3-qnrVC1-bla
OXA-10-aadA1e-qacE⌬1-sul1]).
cmr.asm.org 16
lipopolysaccharide (LPS) biosynthesis, which were correlated with a parallel increase in

novobiocin susceptibility, were also detected in several of these mutants (258). Defi-
cient LPS expression has been involved in increased susceptibility to the most hydro-
phobic quinolones, such as nalidixic acid and flumequine, without affecting those that
are more hydrophilic, such as ciprofloxacin and norfloxacin (241, 259). Furthermore,
while unexplored in these mutants, these alterations in LPS may also play a role in the
final susceptibility levels to especially relevant and last-resort antimicrobial agents,
either increasing or decreasing the final MICs. For instance, a slight increase in colistin
susceptibility has been observed in E. coli carrying mutations affecting core LPS
biosynthesis, while an inverse effect has been observed with tigecycline (260, 261).
Finally, while the relationships between the presence of TMQR and longer hospi-
talization as well as other clinical parameters, including final patient outcomes, remain
to be fully elucidated, different authors have suggested that the presence of the qnr
genes is associated with a trend toward long hospital stays and increased 30-day
mortality (262, 263). In support of this, the presence of TMQR has also been associated
with the poorest clinical response and fatal outcomes in murine models of pneumonia
and urinary tract infection (264, 265).
Therefore, the presence of TMQR is a true risk factor for the development of
quinolone resistance/survival in the presence of high quinolone concentrations even in
the absence of target mutations. Furthermore, their presence may have a direct impact
on the susceptibility levels of unrelated agents by alterations in the expression levels of
specific genes and might have a direct impact on patient management.
The above-mentioned scenarios suggest the appropriateness of including these genes
in routine clinical laboratory procedures, even in the absence of reliable data on their
impact on patient management. This goal is of special relevance for the most sensitive
hospital settings, such as intensive care units, in which commensal microorganisms also
play a key role as antibiotic resistance gene reservoirs (266). Nonetheless, while different
high-throughput approaches, such as DNA microarray technology (267), whole-genome
sequencing (268), or matrix-assisted laser desorption ionization–time of flight (MALDI TOF)
mass spectrometry (269), that are able to be automated and scalable to large numbers of
clinical samples might be implemented (or adapted) for routine detection of TMQR, most
of the currently used methodologies, such as different in-house multiplex PCR approaches
(270, 271), have been conceived for research purposes or to be used in settings with a low
or moderate number of samples for processing.
Molecular Epidemiology of TMQR

TMQR have been largely related to different mobile elements, including plasmids,
transposons, and genomic islands, as well as to the presence of other specific antibiotic
resistance determinants that are cocarried within the same genetic structures (Table 4).
Thus, this concomitant carriage within the same genetic structure of extended-
spectrum ␤-lactamase (ESBL) genes such as blaCTX-M-2, blaCTX-M-6, blaCTX-M-8, blaCTX-M-14,
blaCTX-M-15, blaSHV-2, blaSHV-12, blaVEB-6, and blaVEB-9 (158, 178, 247, 252, 254, 272–278);
carbapenemase genes like blaKPC-2, blaKPC-3, blaKPC-21, blaNDM-1, blaOXA-72, and blaVIM-2
(247, 279–283); plasmid AmpC (pAmpC) genes such as blaCMY-2, blaDHA-1, and blaFOX-5
(245, 276, 284, 285); 16S rRNA methylase genes such as rmtB (158, 286); or other
mechanisms of resistance to unrelated agents is a common fact (Table 4). This fact
might underlie the dissemination of difficult-to-treat pathogenic microorganisms (262,
287). It has also been considered an underlying reason for the role of previous
fluoroquinolone exposure as an independent risk factor for the development of infec-
tions by microorganisms possessing unrelated specific antibiotic determinants such as
blaKPC (288). In this sense, different studies have observed a link between the presence
of blaCTX-M-15, which ranks among the most widely distributed and described ESBLs,
and that of aac(6=)Ib-cr (185, 197, 289, 290). For instance, Pitout et al. found that 34 out
of 63 E. coli strains with the aac(6=)Ib-cr gene also carried the blaCTX-M-15 gene (289).
Accordingly, the neighboring presence of both genes within the same plasmid has
been reported (197, 250). It should be mentioned that other studies, such as those of

Brahmi et al. and Moremi et al., did not find this association (291, 292), probably
suggesting the presence of local differences in the spread of microorganisms/plasmids
related to factors such as specific antimicrobial pressure and geographical factors.
TMQR are frequently encoded within plasmids belonging to different incompatibil-
ity groups and with heterogeneous sizes (Table 4), although surrounding structures are
often similar, suggesting the presence of a limited number of mobilizations of ancestral
chromosomal origin followed by a series of transpositions, recombinations, deletions,
insertions, and every other genetic material arrangement leading to the currently
observed variety. In this sense, the boom of next-generation sequencing approaches
has increased the availability of data related to the presence and distribution of TMQR.
Further molecular epidemiological data are presented in the specific sections devoted
to each TMQR.
Qnr
At the beginning of 1998, Martínez-Martínez and colleagues (15) described the
presence of a TMQR within the plasmid pMG252 in a K. pneumoniae strain isolated in
Alabama in 1994, which was named “qnr” (see “Nomenclature of the Transferable
Mechanisms of Quinolone Resistance,” above). The transfer of this plasmid led to
increases in the quinolone MICs of 8- to 64-fold irrespective of the initial MICs. The
effect was dissimilar among the different quinolones tested, being maximum with
nalidixic acid and minimum with clinafloxacin (15). Thus, when the plasmid was
transferred to E. coli J53, the nalidixic acid susceptibility changed from susceptible
(4 ␮g/ml) to resistant (32 ␮g/ml). Moreover, the authors showed that microorganisms
carrying the qnr determinant were more prone to developing full resistance to fluoro-
quinolones (15). Subsequently, different studies were designed to determine the true
prevalence and relevance of this mechanism of resistance, demonstrating its rare and
low prevalence. Thus, this mechanism was found in only 6 (1 E. coli, 4 K. pneumoniae,
and 1 Klebsiella species isolates) out of 420 Gram-negative microorganisms tested (338
clinical isolates from 19 countries and a series of laboratory strains carrying different
plasmids), with all 6 having been collected in 1994 in Alabama (13). In the subsequent
years, this qnr determinant as well as new qnr variants (Table 5) were increasingly
detected worldwide in different microorganisms, mainly Enterobacteriaceae (138, 293–
297) and a few isolates of Aeromonadaceae (297–300), Moraxellaceae (301) Pseudomon-
adaceae (206, 302), and Vibrionaceae (175, 303, 304), among others (Fig. 5).
Thereafter, some studies were designed using older bacterial collections in order to
detect the presence of these genes in isolates recovered prior to 1994. Thus, the older
transferable qnr gene detected belonged to the qnrB family, being identified in one K.
pneumoniae strain isolated in 1988 in Cordoba, Argentina (305). In the same study,
another qnrB gene carried by a Citrobacter freundii isolate from Brooklyn, NY, was
detected, which had also been isolated in 1988 (305). Nonetheless, in the absence of
specific analysis to determine its genetic environment, and since subsequent studies
have established the possible origin of qnrB genes in the chromosome of Citrobacter
spp. (306), it is uncertain whether this gene was present within a transferable structure
or was an intrinsic resident gene (see “QnrB,” below). In fact, the presence of qnrB60 and
a qnrB pseudogene has been described in the C. freundii collection strains ATCC 6879
and ATCC 8090, respectively (307), both of which were isolated in the late 1920s or early
1930s (308, 309).
It was observed that Qnr also confers slight protection against 2-pyridones,
quinazoline-2,4-diones (both of which are structurally closely related to quinolones),
and spiropyrimidinetriones but has no protective effect against other topoisomerase
type II-targeting molecules such as aminocoumarins (coumermycin A1, novobiocin, and
simocyclinone D8), gyramide A, microcin B17, pyrazolopyridones, or tricyclic pyrimi-
doindoles (310).
Although the presence of Gram-positive chromosomally encoded Qnr has been
described (311), all the currently known transferable Qnr families derive from Gram-
negative ancestors. Therefore, the presence of qnr-related genes has been described in

TABLE 5 Overall view of TMQRa

No. of allelesb
Mechanism TMQRc Litd RefSeqe Size (bp) Yrf Presence of integronsg Ancestorsh
Target protection QnrA 8 8i 218 1998 Y Shewanella spp.
QnrB 88j 81 214 2006 Y Citrobacter spp.
QnrC 1 1 221 2009 Vibrio spp.
QnrD 3 3 214 2009 Morganellaceae?
QnrE 1 2 214 2017 Enterobacter spp.
QnrS 9 14k 218 2005 Vibrio spp.
QnrVCl 9 7 218 2008 Y Vibrio spp.
Efflux system QepA 10 10 511m 2007 Comamonadaceae

OqxAB 14/28 5/7 391/1,050n 2003 Klebsiella spp.o
QacA 1 2p
QacB 1q 2p 2010
pRSB101 2004
Antibiotic modification AAC(6=)Ib-cr ⬎5 7 2006 Y

CrpP ⬎37r 1 2018 Pseudomonadaceae?
Slow growth pKM101

aTMQR, transferable mechanisms of quinolone resistance; Lit, data present in the literature; RefSeq, data present as reference sequence data in GenBank.
bOnly alleles confirmed or proposed to be involved in the development of quinolone resistance.
cOnly confirmed TMQR. When a TMQR was related to the presence of a specific plasmid but no gene-specific nomenclature is available, the name of the plasmid is
indicated.
dBased on GenBank and bibliographic searches. Regarding Qnr, only those included in the Lahey database (formerly at http://www.lahey.org/qnrStudies/) as of 31
December 2018 are shown. This database is no longer available. Other unnamed or erroneously assigned alleles may be found in GenBank (209).
eBased on a RefSeq search (https://www.ncbi.nlm.nih.gov/pathogens/isolates#/refgene/gene_family:XXX, where XXX is the name of the gene) (updated on 12 April
2019).
fPublication of the first allele of the family that has been considered a TMQR, irrespective of the time at which the ability to confer quinolone resistance was
demonstrated. Note that previous conference presentations may have been made and that these presentations may be included in reviews reported prior to the
reported data.
gY indicates that all or several alleles were detected within the integron environment.
hEstablished or proposed original chromosomal sources.
iWhile considered at the Lahey website, QnrA8 is not included in RefSeq. Of note, the only description of this gene was in the S. algae chromosome; therefore,
transferability has not been demonstrated (331).

jQnrB89 has not been included (a high number of amino acid differences with established QnrB alleles has been reported [formerly at http://www.lahey.org/
qnrStudies/], and no data on the exact sequence are provided at either the Lahey website or GenBank).
kQnrS3 has not been included in RefSeq. Of note, the reported sequence lacks the initial amino acid (356).
lWhile QnrVC8 and QnrVC9 were considered at the Lahey website, they are not included in RefSeq. It is of note that in the only description of these genes, they were
located within Vibrio species chromosomes; therefore, transferability has not been demonstrated (363).
mThe proposed QepA8 protein has a 2-amino-acid insertion leading to a final size of 513 amino acids.
nStandard size of OqxA and OqxB, respectively. Note that transferable OqxA and OqxB presenting amino acid insertions have been detected (see Tables 11 and 12).
oKlebsiella pneumoniae and Klebsiella aerogenes (see “OqxAB”).
pNo data about the ability of one of these alleles to extrude quinolones have been reported.
qOnly the QacBIII allele has been associated with the ability to extrude quinolones.
rThe presence of more than 37 closely related alleles with identity levels of ⬎90% has been highlighted (414). Nonetheless, the effect on ciprofloxacin has been
established for only one allele, with the others remaining to be studied.
the chromosomes of different Gram-negative microorganisms, mostly related to water

environments, such as members of the Shewanellaceae and Vibrionaceae families as
well as in other microorganisms belonging to other bacterial families, like the Entero-
bacteriaceae and Xanthomonadaceae, among others (152, 172, 174, 312, 313) (Fig. 5). In
light of these data, different ancestors for current transferable qnr genes have been
proposed (see from “QnrA” to “QnrVC,” below).
In addition to plasmids and transposons, the presence of unexpected qnr transmis-
sion pathways has been described, including the presence of qnr genes within genomic
islands (277), which may be conjugatively transferred under specific circumstances in
the presence of helper plasmids, similar to what occurs with the so-called Salmonella
genomic island 1 (SGI1) (314). Thus, in 2011, a Proteus mirabilis isolate carrying a new
variant of SGI1 (SGI1-V) was described, in which, together with the aacA4 [encoding an
AAC(6=)I enzyme, but no exact allelic variant is indicated], aadB, dfrA1, and blaVEB-6
genes, a qnrA1 gene was present (277). The potential role of bacteriophages in qnr
dissemination has also been reported (315, 316). Thus, by analyzing the role of phages
in the dissemination of antibiotic resistance genes, the presence of qnrA was detected

FIG 5 Main genera in which the presence of qnr genes has been described. This is a nonexhaustive list; the possible presence of nonreported qnr genes
in genera presented in the figure or the presence of qnr genes in genera not presented in the figure should be taken into account. a, genera in which
(Continued on next page)

FIG 6 Description of new qnr alleles (1998 to 2017). Only transferable genes/alleles with a standard name in the nomenclature as of 31 December 2018
according to the Lahey website (formerly at http://www.lahey.org/qnrStudies/) are shown. The reporting year has been considered following the next-priority
order. (A) Date of oldest publication by the describing authors. Note that in several cases, the paper by the original authors might have been published several
years after the original inclusion in GenBank, and therefore, data regarding these alleles may be present in other precedent articles. For example, QnrB6 was
included in GenBank in 2006, being considered when the QnrB nomenclature was normalized and reorganized (319), but the oldest article found by the
describing authors was published in 2009 (457). (B) In the absence of publication data by the describing authors, the oldest article published by any author
was considered. (C) Presence of the allele in meeting presentations by (i) describing authors and (ii) other authors. (D) When neither the published article nor
meeting presentation was found, reporting data have been annotated by the year of the GenBank record. Note that the presence of the allele in GenBank may
precede the time of article publication. In addition, several sequences might be added to the repository at a later time. Note that the absence of an identified
citing article/communication does not preclude the absence of related publications or communications. (E) In the absence of all above-described data, personal
communication was considered if recorded at the Lahey website (e.g., from qnrB84 to qnrB87). qnrE1 was proposed as a new gene in 2017 (176), although qnrB88
was submitted to GenBank in 2016 and also first reported (a meeting presentation) in 2016 (352).
in 18 bacteriophage samples recovered from human wastewater as well as in 18 water

samples from a strongly anthropogenically impacted river but in only 19 out of 28
samples from animal wastewater (315). The same study included qnrS, which was
detected in only 7, 4, and 1 of the above-mentioned human wastewater, river water,
and animal wastewater bacteriophage samples, respectively, but with even higher
densities than qnrA (315).
Qnr Classification
In the first years after the description of qnrA1 in 1998, literature on qnr genes was
scarce, being mostly addressed to describe the presence and prevalence of qnrA1 in
different geographical areas (13, 253, 317) or to advance the knowledge of the mode
of action of qnr (318). Nonetheless, in the mid-2000s (Fig. 6), the presence of new qnr
genes/alleles in GenBank and published reports on qnr suddenly increased. This led to
the presence of different qnr genes with the same name and the subsequent increasing
chaos (319). Therefore, in 2008, a series of rules was implemented to unify the criteria
to define a new qnr allele or gene (319) (Table 6). Thus, the Qnr proteins were classified
within families (genes) and subdivided into alleles based on single or multiple amino
acid differences among them (319).
FIG 5 Legend (Continued)

indigenous qnr-like genes have been described (note that when a qnr gene is present in the chromosome of a nonindigenous microorganism, it is
reported as a TMQR); b, proposed original source of specific transferable qnr; c, microorganisms related to water environments; d, classically classified
together within the family Enterobacteriaceae and classified here in separate genera according to the proposal of Adeolu et al. (347); e, new genus
proposed in 2016, including Escherichia hermannii and Salmonella subterranea (456) (at the time of writing of this review, the genus “Atlantibacter”
was not present in the List of Prokaryotic Names with Standing in Nomenclature [http://www.bacterio.net/index.html]); f, in none of these
Gram-positive organisms are confirmatory sequences for qnrA, qnrB, qnrD, and qnrS available; g, Gram stain variable and phylogenetically closely
related to Clostridium spp.

TABLE 6 Characteristics defining a new Qnr allele/gene

Characteristic(s)
New Qnr element Requisiteb Discardc Optionald Not considered
Allelea Natural source Synthetic origin Increase in MICe Promoter alterations
Full-length sequence Partial sequence Silent mutations
Amino acid change
Identity of ⬎70% (same ancestor)f
Geneg Identity of ⱕ70% (same ancestor)f No effect on MIC Promoter alterations

Increase in MICe Silent mutations
aWithin a defined qnr gene. Allele numeration will be assigned after submission to the qnr repository (https://www.ncbi.nlm.nih.gov/pathogens/submit-beta
-lactamase). Similarly, prior to defining a new qnr gene, it needs to be submitted to the qnr repository. Note that the website manager may not perform continuous
surveillance of the thousands of new articles published monthly or the innumerable new sequences added to GenBank. Researchers need to act responsibly and ask
for an allele assignation prior to any publication and should not pirate or appropriate an allele number in an irresponsible manner, which only contributes to increas-
ing confusion and a lack of trust in publishing results. Similarly, it would be of great interest for journals to ask authors about previous submission to an internet
repository to use the numeration provider by the curator, in order to reinforce the use of correct nomenclature.
bAll these characteristics are needed to classify a new qnr allele/gene.
cCharacteristics invalidating the description of a new qnr allele/gene.
dDesirable but not essential.
eEffect on any quinolone MIC.
fTransferable Qnr genes are named “Qnr” followed by a letter (e.g., QnrA). Chromosomal Qnr should be named with the initials of the microorganism followed by
“Qnr” (e.g., accordingly, qnr from Photobacterium profundum should be named Ppqnr for the DNA and PpQnr for the protein). In addition, it was proposed that if a
chromosomal Qnr has at least 70% identity to one of the established transferable qnr families, it may be named according to transferable or chromosomal name
rules (e.g., SaQnrA3, where Sa represents Shewanella algae). Usually, the latter consideration is applied only for proposed original bacterial sources of established
transferable qnr families.
gThe qnr nomenclature rules published in 2008 (319) considered the presence of either a DNA or amino acid identity difference of ⱖ30% as a requisite to define a
new gene. While this has been considered a general rule, in 2017 qnrB88 was renamed qnrE1 because its original source (Enterobacter instead of Citrobacter) was
taken into account (176), classifying a new gene irrespective of having an amino acid identity of ⬃85% with established QnrB alleles, including QnrB1.
Silent mutations are not considered to determine the presence of new qnr alleles
(319). Nonetheless, the presence of silent mutations may be of epidemiological and
evolutive interest because they may play a role in the diversification of qnr, since further
codon alterations may result in new variants. In this sense, it is of note that in vitro
studies have shown that amino acid changes may alter the levels of resistance con-
ferred by different Qnr proteins (see “In vitro mutations,” below). Furthermore, the
effect of silent differences in DNA sequences in qnr genes on mRNA stability or on the
efficiency of translation to the final protein related to codon usage or other phenom-
ena, which may lead to different levels of Qnr proteins in the bacterial cytoplasm, with
a subsequent effect on final MICs, remains unexplored. In this sense, it has been
observed that increased levels of expression of qnrB and qnrS may be related to higher
MICs of ciprofloxacin (236) (Fig. 4).
Identity criteria (⬍70% identity) were established to determine the different Qnr
families. Accordingly, at present, 7 families of transferable qnr genes have been
described (qnrA, qnrB, qnrC, qnrD, qnrE, qnrS, and qnrVC) (see “QnrE,” below, for levels
of identity between QnrE and QnrB). Nonetheless, while a series of closely clustered qnr
alleles can be found and can even be easily classified within a common family, a series
of gradually divergent alleles, which act as a bridge between different clusters, may
obscure the Qnr family borders. These divergent alleles are the result of natural qnr
sequence divergences within the ancestral host, followed by more than one indepen-
dent mobilization phenomenon, the natural evolution of transferable qnr genes within
different hosts, and the description of transferable qnr alleles/genes with a different,
but closely phylogenetically related, original source (e.g., QnrB and QnrE). All these
forces are not exclusive, and indeed, all act in a simultaneous manner.
A repository website used to number and order new qnr families and alleles (the
Lahey database, formerly at https://www.lahey.org/qnrStudies/) was developed, includ-
ing more than 100 different qnr alleles (Table 5). Similar to what occurred on July
2015 with the repository of ␤-lactamases (https://www.lahey.org/Studies/), in 2018,
this repository was transferred to the NCBI for Qnr nomenclature maintenance
and future gene/allele assignations, and the original Lahey database is no longer
online. Thus, ␤-lactamase, qnr, as well as mcr gene/allele assignations are cur-

rently centralized at (https://www.ncbi.nlm.nih.gov/pathogens/submit-beta

-lactamase). Meanwhile, to my knowledge, no database has compiled the chromo-
somal qnr genes, except for chromosomal qnr genes present in the bacterial chromo-
some of S. maltophilia described at a website (http://www.icms.qmul.ac.uk/centres/
immunologyandinfectiousdisease/Smqnr%20Web%20v2.htm) that seems to have
disappeared (I was unable to find this website) but existed at the beginning of the
2010s (320).
Qnr Families
Although the presence of Gram-positive chromosomally encoded Qnr proteins has
been described (311, 321), all the currently known transferable Qnr families derive from
Gram-negative ancestors (see from “QnrA” to “Chromosomal Qnr,” below).
As mentioned above (see “Nomenclature of the Transferable Mechanisms of Quin-
olone Resistance”), the names of transferable Qnr determinants have been assigned in
a mixed manner. Thus, some follow an alphabetical order according to the first
description, while others have been named based on the microorganisms from which
they were first recovered, irrespective of the ordinal moment and the true prevalence
in this microorganism. The next 7 subsections are strictly ordered alphabetically.
Therefore, the order in which the different families are presented does not preclude the
order described in time.
QnrA. As mentioned above, the qnrA gene, which encodes a 218-amino-acid
protein, was the first well-established TMQR (15). Further studies determined that this
qnr gene is located in an integron-like environment (318). The integron containing
qnrA1 was fully sequenced in 2007, confirming the presence of qnrA1 in a complex class
1 integron downstream from the first qacEΔ1-sul1, between 2 ISCR1 elements (284). The
same study also highlighted the presence of qnrA1 in other complex integrons (284).
The association between ISCR1 and qnrA1 has been largely reported, although in most
cases, only the first ISCR1 is present (253). Furthermore, other genetic structures lacking
the presence of ISCR1 have also been described (322). The presence of qnrA between
2 ISCR1 elements may facilitate spontaneous (or induced under quinolone pressure)
qnrA gene duplication, with the subsequent effect on the final MIC of quinolones (251).
Thus, when the in vitro-selected pMG252 plasmid-derived mutant pMG252A was
cloned into an E. coli J53 background, the qnrA1 expression level and the MIC of
ciprofloxacin rose 2.2- and 8-fold, respectively, higher than those related to the
presence of pMG252 (258). Recent reanalysis and sequencing of pMG252A showed that
these findings were due to the presence of 4 additional qnrA1 copies after the original
ISCR1-qnrA-qacE⌬1-sul1-ISCR1, following the scheme qnrA-qacE⌬1-sul1-ISCR1 (251). Of
note, this phenomenon might be extended to other TMQR placed between 2 insertion
sequences. For reading of literature published before 2006, note that ISCR1 is usually
referred to as orf513 or orf341. Additionally, the term “CR” for “common region” may
also be present (196, 323–325).
Although variants of qnrA1 containing silent mutations were detected in 2003 (253),
until 2004, no other qnrA allele (qnrA2) was described (GenBank accession number
AY675584). Nevertheless, to my knowledge, there has been no published report by
sequence authors, with the first report including QnrA2 data, together with those of
QnrA3, QnrA4, and QnrA5, being published in 2005 (172).
Currently, 8 qnrA alleles have been described in accordance with nomenclature
rules, mainly described within complex integron-like genetic environments (246, 284,
325–328), while a search of GenBank detected other new transferable QnrA alleles
together with 2 new chromosomal Shewanella algae qnr variants (see the next para-
graph). Of note, QnrA8 recorded previously in Lahey’s repository is not in the RefSeq
list, probably because no description within a plasmid or other transferable genetic
structure has been made.
Shewanella species has been proposed as the chromosomal ancestor of this Qnr
family. Thus, QnrA1 (329) and QnrA2 (GenBank accession number BAF95541) have been
detected in the chromosome of Shewanella putrefaciens, while QnrA2, QnrA3, Qnr4,

FIG 7 Example of a complex integron containing qnr determinants. In both panels, the first variable region is identical. Note that in addition to the qnr
determinants, other TMQR such as aac(6=)Ib-cr may be also present. (A) Complex integron containing a typical ISCR1 element (note that in older studies, ISCR1
is referred to as orf513 or orf341) after the classical 3=-end region of class 1 integrons (qacEΔ1-sulA) and just before the qnrB6 determinant environment (between
psp and sap clusters) present in the second variable region. (Adapted from reference 458 with permission.) (B) Complex integron in which ISCR1 has been
replaced by an IS26 element. Note that the environment of qnrB4 slightly differs from that in panel A (the sap cluster has been lost). (Adapted from reference
245 with permission from Elsevier.)
QnrA5, and QnrA8 have been identified in that of S. algae (172, 330, 331). QnrA7 has
also been detected in S. algae both in the chromosome (GenBank accession number
CP018456) and within a 33-kb plasmid (332). A GenBank search using QnrA1 (GenBank
accession number AAL60061) also detected other QnrA alleles within the chromosome
of S. algae, including the sequences under GenBank accession numbers WP_044735234
(333) and WP_045283443 (334).
QnrB. The first qnrB gene was described within the pMG298 plasmid in a South
Indian K. pneumoniae isolate (335), being the third transferable qnr family described. In
the same study, the second qnrB allele (qnrB2) was detected in isolates from the United
States when designing primers to determine the prevalence of qnrB in different
microorganisms (335). Since then, the number of new qnrB alleles has been continu-
ously rising, with a total of 87 unique sequences with an assigned allele numeration in
the Lahey database as of 31 December 2018 and, as remaining qnr genes, an uncertain
number of unnoticed alleles (209). Similar to what has been described for the qnrA
genes, qnrB may be located within a complex integron environment associated with
ISCR1 or other insertion sequences like IS26 (245, 275, 336) (Fig. 7). In addition, other
dissemination pathways, such as transposons like Tn2012 (formed by ISEcp1C and
qnrB19) or the so-called KQ element (for KPC and Qnr), have been described, in which
the acquisition of qnrB19 has been suggested to be related to ISEcp1-like mobilization
(283, 336, 337).
Although in 2005, two different sizes for QnrB1 (226 amino acids long) and QnrB2
(214 amino acids long) were described (335), in 2008, consensus was achieved regard-
ing the use of the initial codon present in QnrB2 as the initial QnrB family ATG because
of its commonness to all the QnrB proteins described (319). Thus, caution is needed
when analyzing QnrB in order to ensure the use of the correct size and amino acid
numeration.
In 2004, the presence of a qnrB gene was detected during marine metagenomic
studies, leading to the proposal that an unknown marine microorganism may be the
original source of QnrB (338, 339). Nonetheless, taking into account the high prevalence
and diversity of QnrB, together with the lack of surrounding mobile elements in
Citrobacter spp., members of the C. freundii complex are considered to be the original
source of QnrB (306).
Within the genomes of the C. freundii complex (as well as in most of the transferable
QnrB proteins detected), the genetic environment of qnrB is highly conserved, being
located between two gene clusters, the psp (phage shock protein) cluster downstream
and the sap (sensitivity to antimicrobial peptides) cluster upstream (306, 307). These
clusters are contiguously present in the chromosomes of other Enterobacteriaceae,
including other Citrobacter spp. such as Citrobacter koseri and Citrobacter rodentium, in
which no qnrB is present. In view of these findings, it was proposed that a common
ancestor of the C. freundii complex had acquired an exogenous qnrB-like gene between
the psp and sap clusters, which was thereafter maintained or partially deleted, leading

to the presence of pseudogenes (307). Further mobilization phenomena led to the

transfer of qnrB to plasmids, which were then acquired by other microorganisms,
resulting in the current widespread scenario.
Although not demonstrated, it seems evident that this spread from a member of the
Enterobacteriaceae family would strongly favor the wide dissemination of this qnr family
within Enterobacteriaceae, which are probably the microorganisms most commonly
isolated and studied, leading to their current status as the most frequently described
(and numerous) qnr family worldwide.
QnrC. To date, only one allele of QnrC has been described, first detected in a
plasmid (pHS10) from P. mirabilis (340). This Qnr is slightly larger than the remaining
transferable Qnr proteins, being 221 amino acids long, similar to the lengths of some
chromosomal Qnr proteins from different Vibrio spp. Accordingly, the origin of QnrC
has been proposed to be among Vibrionaceae (340). Indeed, different VpQnr and VrQnr
proteins (chromosomal Qnr of Vibrio parahaemolyticus and Vibrio rumoiensis, respec-
tively) present amino acid identity levels ranging from 94 to 97% (e.g., GenBank
accession numbers ODZ33109.1 and OEF25096). Furthermore, a chromosomal Qnr was
found (GenBank accession number WP_105901077.1) in a recently sequenced Vibrio
gangliei isolate (GenBank accession number NZ_PPSN01000001), differing in 9 bp
compared to QnrC and resulting in 1 amino acid change, thereby presenting DNA and
amino acid identities of 98.6% and 99.5%, respectively. This origin within Vibrionaceae
produces identity levels of QnrC with some members of the QnrVC family of more than
70% (210) and highlights the recent suggestion that the ancestral microorganism
should be taken into account to define new transferable qnr families (176).
To date, QnrC seems to be infrequent, although it has been described in different
genera, including the above-mentioned genus Proteus (340) as well as in Escherichia
(341), Klebsiella (342), and Shigella (343) (Fig. 5).
QnrD. QnrD was first described as being encoded in a small plasmid of 4.3 kb
(p2007057), which was isolated from 4 S. enterica strains belonging to serovar Bovis-
morbificans (3 strains) and serovar Kentucky (1 strain), isolated in China in 2006 or 2007
(344). QnrD is 214 amino acids long. In contrast to other Qnr proteins, when cloned into
E. coli DH10B, the first studies showed a null or very limited effect on the MIC of nalidixic
acid (only a 2-fold increase, from 2 to 4 ␮g/ml) and a higher impact on final ciprofloxa-
cin MICs, which increased from 0.002 to 0.06 ␮g/ml (increase of 32-fold) (344, 345).
Nonetheless, further studies on the cloning of QnrD in E. coli TOP10 showed slightly
higher increases in the MIC from 2 to 8/16 ␮g/ml for nalidixic acid (346).
At present, 3 alleles have been formally described, while other QnrD family members
are present in GenBank (e.g., GenBank accession numbers WP_084978381 and
WP_108479726). QnrD has been detected in a variety of microorganisms (Fig. 5),
including Ochrobactrum anthropi (GenBank accession numbers CCV01662.1 and
CCU60984.1, among others) belonging to Brucellaceae, in which Qnr proteins have
been scarcely detected. Nonetheless, QnrD proteins have been described as being
especially prevalent in members of the genera Proteus and Providencia, belonging to
the Proteeae tribe (currently proposed to be reclassified as the new family Morganel-
laceae [347]), encoded within small (⬃2.6- to ⬃5.2-kb) nonconjugative plasmids of an
undescribed incompatibility group, usually linked to an open reading frame (ORF)
(ORF-2) of unknown function (345, 346, 348–351). Thus, while Guillard et al. detected
QnrD in 7 out of 332 (2.1%) Morganellaceae isolates (349), in more-recent studies, the
presence of qnrD was observed in 40 out of 203 (19.7%) Morganellaceae isolates (348)
and in 19 out of 24 (79.2%) Proteus species isolates (351). Considering these findings,
it has been proposed that the origin of QnrD lies within an as-yet-unidentified member
of this bacterial family, and different Proteus spp., Providencia spp., and Morganella spp.
may play a role as intermediate reservoirs from which QnrD has expanded to other
microorganisms (346, 348, 349). However, as yet, this remains to be demonstrated.
Although there is no information on the specific microorganisms used as QnrD
donors, the above-mentioned role of phages in the dissemination of QnrD has been
experimentally observed by the transduction of qnrD into E. coli JM109 (348).

QnrD is one of the few TMQR that has been described among Gram-positive
microorganisms. Thus, in a study aimed at determining the presence of antibiotic-
resistant microorganisms in treated and untreated river water, qnrD was detected in
Bacillus spp. and Kurthia spp. (167). Unfortunately, no attempt to confirm these data by
DNA sequencing and to determine either the exact genetic environment or the exact
allelic variant of qnrD was performed, and no further data are available.
QnrE. In the middle of 2017, a K. pneumoniae strain isolated in 2007 in Argentina
exhibiting low-level quinolone resistance, wild-type GyrA, and negative results when
TMQR were sought was reported. Further analysis showed the presence of a 645-bp
ORF carried within an IncM1 transferable plasmid (pKp1130; GenBank accession num-
ber KY073238) (176). This ORF showed an average identity of 75% with members of the
QnrB family, and a literature search showed 100% identity with qnrB88, which was
isolated in Brazil from a K. pneumoniae plasmid (pKp145-11b; GenBank accession
number KX118608) (352). Thereafter, another K. pneumoniae isolate carrying this gene
within an IncM1 plasmid (pKP41M) as well as 3 S. enterica isolates belonging to
serotypes Enteritidis, Infantis, and Newport also carrying qnrE1 within an IncM1 plasmid
were again described in Brazil (273, 353). A further search of GenBank showed the
presence of qnrE1 within S. Typhimurium (e.g., GenBank accession number KYE08263),
C. freundii (e.g., GenBank accession number PUU65120), and other K. pneumoniae
isolates. Moreover, a variant with only 2 amino acid differences currently recorded as
QnrE2 in GenBank (GenBank accession number WP_078207746.1) is present within an
E. coli plasmid (pEC422_1; GenBank accession number CP018961) as well as (although
initially recorded as QnrS1) a whole-genome sequence of K. pneumoniae (GenBank
accession number UJVU01000046).
Although, according to the rules of qnr gene nomenclature, this gene should be
considered a member of the qnrB family (Table 6), QnrE has been classified as the first
member of a new family (qnrE). An in-depth analysis showed high identity with the
chromosomal qnr gene of Enterobacter spp., also suggesting that ISEcp1 is responsible
for gene mobilization (176) and therefore has a different ancestral origin than other
qnrB genes. Notwithstanding, this finding highlights the need to use the concept of
gene family with caution as well as to advance toward the introduction of the concept
of original bacterial chromosomal source to nomenclature rules. Indeed, there are
numerous genomic data for different Enterobacter spp., including an Enterobacter kobei
Qnr protein (GenBank accession number OTW32454) with 100% amino acid identity
with QnrE1. In addition, a series of closely related qnr genes (even with ⬎85% identity
in either DNA base pairs or amino acids) are also present in other bacterial genomes,
especially within the genus Serratia, such as Serratia plymuthica (e.g., GenBank acces-
sion number AGP44145) and other Serratia spp. (e.g., GenBank accession number
OKP25762), as well as in the genomes of other Enterobacteriaceae such as Lelliottia spp.
(e.g., GenBank accession number ASV55492) and Buttiauxella spp. (e.g., GenBank ac-
cession number KFC78735).
Curiously, at present, all transferable qnrE genes (those present outside a potential
indigenous bacterial source) for which the geographical source is available (18 out of
20 GenBank-recorded sequences) have been described in South America, within Citro-
bacter spp. from Argentina, Klebsiella spp. from Argentina and Brazil, Salmonella spp.
from Brazil, and E. coli from Ecuador. It is likely that upon routine screening of this gene,
the number of microorganisms carrying QnrE variants, alleles described, and geograph-
ical locations would be greatly increased.
QnrS. QnrS was first described in 2006 as being encoded within a conjugative
plasmid of 47 kb (pAH0376) of an S. flexneri 2b strain isolated in Japan in 2003 (171).
Studies performed in subsequent years showed a low, albeit increasing, prevalence of
QnrS and a wide geographical distribution. Thus, QnrS was described in microorgan-
isms such as S. enterica, E. coli, and Enterobacter cloacae, among others (328, 354). Since
then, up to 9 QnrS alleles have been described and numbered in a previous Internet
repository (https://www.lahey.org/qnrStudies), and at least 5 other alleles (QnrS10 to
QnrS15) are present in GenBank (209), being described in a great variety of microor-

ganisms and environments (133, 203, 209, 245, 297, 300, 355). Of note, QnrS3 is not
numbered in RefSeq, probably because the reported sequence lacks the initial amino
acid (356).
The mobilization and spread of qnrS alleles have been mediated by structures such
as insertion sequences such as IS2, IS26, and ISEc12 (a member of the IS21 family) (272,
354, 357, 358). Additionally, qnrS has also been described as occurring near, but not
within, Tn3-like structures carrying blaTEM-1 (171, 354). In this sense, Kehrenberg et al.
described the plasmid pINF5 from Salmonella enterica serovar Infantis which, after a
Tn3-like structure, carried a defective ISEc12 element followed by a qnrS2 gene, an
internal segment of the CS12 fimbrial gene cluster of E. coli, and a defective IS26
element (354).
The origin of QnrS has been proposed to be among aquatic microorganisms.
Thus, in 2007, the presence of chromosomal Qnr was observed in Vibrio splendidus,
with identity levels of 83.1 to 83.9% with QnrS1 and 87.1 to 87.6% with QnrS2 (the
2 QnrS proteins described at that time) (312). Thereafter, Vibrio species sequences
presenting higher identity levels have been detected. For instance, 97% and 95.5 to
96% amino acid identities with chromosomal Qnr from Vibrio mytili (GenBank
accession number KIN11186.1) and Vibrio parahaemolyticus (GenBank accession num-
bers WP_029802054.1 and WP_029823919.1), respectively, have been observed. Fur-
thermore, in a V. parahaemolyticus isolate from Malaysia, a Qnr protein (GenBank
accession number KKF68274.1) has been detected, located between transposases
having 100% amino acid identity with QnrS1. Despite being classified as “genomic,” the
size of the containing DNA sequence (2,178 bp long) allows the possible presence of
this qnr gene within a plasmid environment.
QnrVC. Although qnr genes were described within the genomes of Vibrionaceae as
early as 2005 (171, 174), the presence of a new transferable qnr family within an
integron environment in V. cholerae was not shown until 2008 (175). This transferable
Qnr variant was subsequently detected in other Vibrionaceae (303, 304, 359, 360) and
in other bacterial families such as Aeromonadaceae (361) and Moraxellaceae (362), even
within plasmids or in integron environments. Despite these evidences, the presence of
this transferable qnr family was not proposed and subsequently included in the Lahey
database until 2013 (210).
Nine different QnrVC alleles (QnrVC1 and QnrVC3 to QnrVC10), which have a length
of 218 amino acids, have been classified by the Lahey website. Of these, at present,
QnrVC8 and QnrVC9 are not included as numbered QnrVC variants in RefSeq, being in
fact present within the Vibrio species chromosome (363). Note that qnrVC2 is not
considered in the list because of the presence of 3 base insertions and 1 deletion (361)
leading to a frameshift and premature stop, erasing its functionality. Similar to QnrB,
another possible initial codon may be present 13 amino acids before the initial ATG
codon (e.g., GenBank accession number APA29731).
These alleles have been described worldwide in plasmid and integron environ-
ments, either in the first variable region of a classical class 1 integron or downstream
from ISCR1 within a complex class 1 integron (274, 364). In this sense, it is worth
mentioning that qnrVC may be included in a gene cassette with an attC site (175, 231,
361). In contrast to classical integron gene cassettes, qnrVC gene cassettes may possess
their own promoter, which allows them to surpass the decreased levels of expression
related to a delayed position within the overall integron or to the absence of the strong
promoter P2 (231).
It is of interest that QnrVC may be subdivided into two main groups, which are
composed of (i) QnrVC1, QnrVC3, QnrVC6, QnrVC10, and one P. aeruginosa sequence
erroneously classified as QnrVC7 (GenBank accession number AWT08553), in which the
more divergent allele is QnrVC3, differing by 4 and 5 amino acids with respect to
QnrVC1, QnrVC6, and QnrVC10 and QnrVCAWT08553, respectively, and therefore with
identity levels of 97 to 99.5%, and (ii) QnrVC4, QnrVC5, and QnrVC7, in which the
maximum difference is 3 amino acids between QnrVC5 and QnrVC7. The identity levels

of these alleles are around 98.5 to 99.5%. QnrVC1-like and QnrVC4-like proteins differ
by a minimum of 40 amino acids, with a maximum identity of 81.6%.
At present, QnrVC has been detected in additional genera within the Enterobacte-
riaceae (E. coli, Enterobacter spp. Citrobacter spp., Klebsiella spp., and Salmonella spp.)
and Pseudomonadaceae (P. aeruginosa and P. putida), among others (206, 231, 249, 302,
350, 364–366) (Fig. 5).
Chromosomal Qnr. The presence of chromosomal qnr genes was first observed in
2005 in Photobacterium profundum and Vibrio vulnificus (171). The same year, the
chromosomal qnr gene of a strain of V. parahaemolyticus was cloned in a pUC118-
derived plasmid and introduced into an E. coli isolate (174). The wild-type cloned gene
does not affect the MIC of quinolones, but a mutant cloned gene with a single amino
acid change, C115Y, accidentally introduced during PCR procedures showed 8- to
16-fold increases in the MICs of nalidixic acid, ciprofloxacin, and levofloxacin. After-
wards, the effect of this point mutation was confirmed by mutagenesis studies (174).
In subsequent years, a great number of chromosomally encoded Qnr-related pro-
teins have been detected, in both Gram-negative and Gram-positive microorganisms,
and their ability to confer resistance to quinolones has been confirmed in most cases
(215, 367). Thus, the 2008 Qnr nomenclature rules, in order to differentiate a plasmid-
encoded from a chromosomally encoded Qnr protein, proposed that the initials of the
microorganism be added before chromosomal Qnr (e.g., EfsQnr for chromosomal Qnr
of Enterococcus faecalis) (Table 6).
Among microorganisms possessing chromosomal Qnr, a high heterogeneity of
chromosome-encoded Qnr proteins of S. maltophilia was observed. Thus, 11 different
alleles were sequenced when SmQnr was detected (368). This finding was thereafter
confirmed (369, 370), and as mentioned above (see “Qnr Classification”), the develop-
ment of a website repository to bring order to the SmQnr nomenclature was proposed
(320). The number of SmQnr alleles has increased enormously in the last years, with
⬃150 different SmQnr alleles being detected in a GenBank search performed at the
time of this review.
Although indigenous chromosomal Qnr proteins have been detected in microor-
ganisms, such as in the above-mentioned E. faecalis and C. freundii (306, 311, 321), a
high number has been found in microorganisms from water environments (367). In fact,
as indicated when the different Qnr families are presented in this review, 4 out of 7 of
the currently established transferable Qnr families (QnrA, QnrC, QnrS, and QnrVC) are
derived from chromosomes of water-related microorganisms (367).
Qnr Structure
Qnr proteins are dimeric proteins belonging to the pentapeptide repeat protein
(PRP) family, which encompasses thousands of proteins present in more than 1,500
eukaryotic or prokaryotic organisms (371, 372).Thus, the PRP family includes MfpA-like
proteins, a chromosome-encoded Mycobacterium species protein group able to confer
slight protection against the action of quinolones (373, 374), and McbG from E. coli,
which is involved in resistance to microcin B17, a natural topoisomerase II inhibitor
(375). This protein family is characterized by a tandem repeat of 5 amino acids, in which
the residue located in a central position is indicated as “i.” Those on the right are
indicated by adding 1 or 2 (i⫹1, i⫹2), and those on the left are indicated by subtracting
1 or 2 (i⫺1, i⫺2), leading to the structure i⫺2, i⫺1, i, i⫹1, i⫹2 (372). The typical PRP motif
follows the amino acid scheme i⫺2 (S, T, A, or V), i⫺1 (D or N), i (L or F), i⫹1 (S, T, or R),
i⫹2 (G) (372).
Although data are inferred from the limited number of Qnr crystallography studies,
it has been observed that the Qnr dimer has a rodlike form in which each monomeric
structure folds into a right-handed quadrilateral ␤-helix (376, 377). In this quadrilateral,
the PRP amino acid in position i interacts with the amino acid i⫺2, stabilizing the
structure; both residues i and i⫺2 are oriented toward the internal quadrilateral surface,
while the remaining residues are oriented toward the exterior, resulting in a usual
anionic surface (378). This quadrilateral structure has 9 square repeating units, called

coils, numbered from 0 to 9, and these coils are stacked on each other, leading to a
4-faced protein (372). Thus, each coil has 4 faces numbered from 1 to 4, and 5 amino
acids forming a PRP motif are presented on each face (372, 376). Most of the coils
present a type II turn, which clusters toward the C-terminal region, while a few (7 in
QnrB1) have a type IV turn, being located on faces 2 and 4 toward the N-terminal region
(376). Of these coils, the first (coil 0) is capped in some Qnr proteins, such as QnrB1, due
to the presence of the noncanonical PRP residues E8 and E18 at the i⫺2 position (376).
The last (coil 9) is also capped in all the Qnr proteins analyzed (376, 379) because of the
presence in the protein C terminus of the dimerization module formed by the structure
strand (␤)/helix (␣)/strand (␤) (376, 377, 380). In this structure, the orientation of each
subunit is flexible thanks to the small, ⬃730-Å2/subunit, and hydrophobic contact area
(376).
In transferable as well as in several chromosomally encoded Qnr proteins, the
quadrilateral structure is broken by 2 outward-projecting loops, named loop A and loop
B, present between the second and third faces of coil 2 and between the fourth face
of coil 4 and the first face of coil 5, respectively. These loops account for 8 amino acids
(loop A) (from amino acid 46 to amino acid 53) and 12 amino acids (loop B) (from amino
acid 102 to amino acid 113) (371, 376, 377) (Fig. 8). These loops are essential for the
protective action of Qnr. Thus, in QnrB1 and AhQnr (the Qnr-like protein encoded in the
chromosome of Aeromonas hydrophila), it has been shown that a deletion of loop A
produces a strong decrease in the protective action of Qnr, while a deletion of loop B
(or of both loops) leads to a full loss of Qnr protection (376, 377). In this line, point
amino acid changes within loops may also lead to deleterious effects on protective
activity (see “In vitro mutations,” below) (Table 7). Nonetheless, it has been observed
that EfsQnr (chromosomal Qnr of E. faecalis) has no loop, retaining its protective action
(381). This finding has been related to a series of peculiarities in the N-terminal region,
in which the first 26 amino acids are not part of the quadrilateral ␤-helix (381). Thus, the
first 18 amino acids of EfsQnr are extended over the ␤-helix, with which they interact,
while amino acids 19 to 26 transverse the diagonal of the ␤-helix (381). Of note, the
deletion of the first 17 amino acids strongly affects the protective action of EfsQnr (381).
Original Qnr Function

It has been suggested that the original Qnr function is similar to that of GyrI (a
protein also able to confer slight protection against quinolones). GyrI has been related
to bacterial protection against natural topoisomerase II inhibitors such as CcdB and
ParE (not to be confounded with topoisomerase IV subunit B). Both proteins belong to
addiction systems involved in plasmid maintenance (382). Nonetheless, further studies
have described the inability of Qnr to protect DNA gyrase from the action of these
toxins and the lack of an effect of these toxins on the quinolone protection conferred
by Qnr or on quinolone susceptibility levels (383).
Other authors have considered the possible involvement of several Qnr proteins,
such as QnrB and QnrD, in the bacterial response to DNA damage (384). This proposal
considers the presence of a lexA box in the Qnr promoter region of these genes (but
not in that of other Qnr variants), which results in the expression of Qnr in a LexA/
RecA-dependent manner under SOS system control (385, 386).
Another proposal focused on the original Qnr function in the water-related envi-
ronment of several Qnr ancestral microorganisms. Thus, it has been observed that qnrA
is overexpressed with cold shocks, suggesting an adaptive role favoring the survival of
bacteria in water environments at low temperatures by regulating negative DNA
supercoiling through the stabilization or modulation of the activity of DNA gyrase or
topoisomerase type III (330). In this sense, it should be mentioned that most Shewanella
spp., the ancestral source of QnrA, are psychrotolerant and are able to grow at
temperatures of ⬍5°C (387).
Nonetheless, despite these suggestions, in the absence of definitive studies, the
original function of Qnr remains unknown.

FIG 8 Structure of Qnr. (A) Sequence of QnrB1. The sequence is presented under 4 columns, one for each of the four faces of the
right-handed quadrilateral ␤-helix. At the top are the faces (each one marked with a different color; note that the colors are maintained
in the 3 panels) as well as the naming convention for each PRP residue. The positions of loop A and loop B are marked (*, loop A; **, loop
B). The sequences of both loops are at the bottom of the panel. Highlighted in salmon is the N-terminal ␣-helix. (B) Structures of 4 Qnr
proteins, QnrB1, MfpA (PRP from Mycobacterium spp.), AlbG (PRP produced by Xanthomonas albilineans), and EfsQnr (chromosomal Qnr of
Enterococcus faecalis). MfpA is able to confer slight resistance to quinolones, while AlbG results in resistance to albicin (a natural
topoisomerase inhibitor). (C) QnrB1 dimeric rodlike structure. The amino acid positions of loop A and loop B are indicated. A diamond shows
the molecular 2-fold symmetry. Type II turn-containing faces are shown as spheres, and type IV-containing faces are shown as strands.
(Reproduced from reference 376 with permission of the publisher.)

TABLE 7 Effect of specific amino acid substitutions and deletions at loops A and B on
Qnr protection levelsa
Change(s) in indicated Qnr causing a decrease in protection
Position(s) within TR QnrA1 QnrB1 QnrC1 QnrS1
Loop A ⌬A41–G56
⌬I49–E55
⌬S51–G56
Y46A
ΔY46–Q51
S50A
ΔG56/D ⌬G53A/D/E ⌬G56D/E
Loop B N103A
M104A
⌬M104–S113
I105A V108A
ΔT106 S109A
ΔT106–T107
ΔT107
ΔR108
⌬T106–R108
ΔT107-R108
M112A
W110A Y113A
F114D F111A/D F114A
C115Y C112A/Y C115A/Y
R58H ⴙ R87H ⴙ C112Yb ⴙ N178Y
S116D S113A/D S116P S116A
Loops A ⫹ B ⌬Y46–Q51 ⴙ ⌬M104–S113

aAmino acid substitutions are listed from top to bottom in the direction from the N to C termini. Changes in
the same row are analogous to each other. The amino acids highlighted in boldface type are those leading
to a full loss of Qnr activity and a subsequent lack of an effect on the final quinolone MICs. Note that
cloning in different vectors may slightly affect the final full or partial loss of activity. The amino acid change
is reported only when there is a positive or negative effect of at least 4-fold on the MIC of the quinolones
described. Note that different studies have determined the Qnr effect on different quinolones. Loop A, amino
acids 46 to 53 (QnrB) and amino acids 49 to 56 (QnrA, QnrC, QnrS, and QnrVC); loop B, amino acids 102 to 113
(QnrB); TR, tandem repeat; Δ, deletion (based on data from references 234, 235, 376, and 391–394).
bThe amino acid change C
112Y is located in loop B.
Mechanisms of Qnr Action

The exact manner as to how Qnr interacts with DNA, type II topoisomerases, and/or
quinolones to confer quinolone protection remains controversial, and further studies
are needed to establish the definitive mode of action of Qnr.
Initial studies to determine the mode of action of Qnr showed that Qnr minimizes
the action of quinolones by interacting with type II topoisomerases (388, 389). Further-
more, it was observed that this interaction did not need either DNA or quinolones,
suggesting the presence of different possible mechanistic explanations (388, 389). Thus,
an alteration of the quinolone-binding pocket conformation was considered, which
hinders further quinolone-target interactions and leads to a reduction of the presence
of the cleavage complex among quinolones, DNA, and DNA gyrase/topoisomerase IV
(388, 389). Other options have also been considered, such as the destabilization of
these cleavage complexes, which subsequently allows DNA replication, or the reduc-
tion of the interactions between DNA and DNA gyrase, leading to a lower number of
replication forks (388, 389).
In order to answer these questions, Xiong et al. (377) analyzed the structure of
AhQnr in silico, and its interactions with DNA gyrase led to the proposal of an
interaction model in which Qnr is located within the DNA gyrase structure interacting
by electrostatic charges through faces 1 and 2. In this model, loops A and B interact
with the topoisomerase-primase (TOPRIM) domain of GyrB and the GyrA “tower,”
respectively, although a specific orientation of the GyrA and GyrB subunits is needed
(377). The authors propose that this specific GyrA/GyrB orientation is favored when

TABLE 8 Effect of specific amino acid deletions at PRP

units on Qnr protection levelsa
Deletion in indicated Qnr causing a decrease in protection
QnrA1
ΔD2–Q10
ΔD2–S21
ΔL187–D218
ΔL207–D218
QnrB1
ΔM1–F15
ΔM1–I20
M205–G214
ΔI210–G214
ΔV212–G214
QnrC1
ΔI11–S20
ΔN77–G96
ΔC137–K156
aIn all cases, these deletions lead to a full loss of Qnr activity and a
subsequent lack of an effect on the final quinolone MICs. Note that
different studies have determined the Qnr effect on different
quinolones. Deletions within loop A or B are reported in Table 7.
Deletions of single amino acids are reported in Table 9 (based on
data from references 234, 235, 376, and 391–394).
quinolones interact with topoisomerase and subsequently allows Qnr to interact with
and disrupt the complex between quinolones and topoisomerase (377), and the latter
recovers its catalytic activity.
At around the same time, working with a crystallographic QnrB1 model, Vetting et
al. (376) proposed a model in which Qnr acts in a posterior step, when the DNA-poison-
topoisomerase is cleaved, destabilizing the cleavage complex and restoring DNA
replication.
Subsequent studies analyzing the effect of point mutations of either loop A or loop
B found no correlation between the Qnr-topoisomerase interaction and final protection
levels, proposing that the loops are not involved in direct interactions with topoisom-
erase but rather are involved in proper Qnr positioning in gyrase, blocking the access
of quinolones. Thus, when the Qnr-gyrase complex interacts with DNA, Qnr is removed,
and the enzyme becomes catalytic (390).
In vitro mutations. As mentioned above, the first evidence of the effect of point
mutations on quinolone protection levels conferred by Qnr determinants was observed
in 2005 due to a PCR accident which produced an amino acid change, C115Y, during
cloning of a V. parahaemolyticus chromosomal Qnr determinant (174). Further studies
analyzing the effect of the same amino acid change in QnrA1 and QnrS1 showed a
different scenario, in which despite both mutated Qnr proteins exhibiting a certain
degree of protection, this was lower than that for parental Qnr (391). Along the same
line, when this mutation was generated in the equivalent position of QnrB1 (C112), a full
loss of Qnr activity was observed (392) (Table 8).
Similar differences in final quinolone MICs were observed when different S. malto-
philia chromosomal Qnr alleles were cloned (368). Thus, SmQnr5 does not affect the
MICs of norfloxacin, ciprofloxacin, sparfloxacin, or gatifloxacin but rather has an almost
imperceptible effect (ⱕ2-fold) on the MICs of nalidixic acid, levofloxacin, and moxi-
floxacin. Meanwhile, except in the case of nalidixic acid, the effect of SmQnr6 leads to
⬎5-fold increases, reaching increases of up to ⬎62-fold for the MICs of sparfloxacin
(from ⬍0.002 to 0.125 ␮g/ml) (368).
Rodríguez-Martínez et al. (392) analyzed the effects of different amino acid codon
changes by random and directed mutagenesis. Although most of the amino acid
variations detected led to decreased or null Qnr protection, the results showed that in
QnrS1, the amino acid change D185Y increases the MICs of ciprofloxacin and moxifloxa-

cin in E. coli 4-fold (both from 0.125 to 0.5 ␮g/ml), and increases of 2-fold were observed
when norfloxacin, ofloxacin, and levofloxacin were tested (392). In the same study, it
was also observed that the effect of the same substitution led to different final results
when introduced into different Qnr families. Thus, the D185Y amino acid change had no
effect on the final MICs when introduced into QnrA, while it negatively impacted the
Qnr protective role when introduced into QnrB (392). Furthermore, while the deletion
of Gly56 in QnrA results in a reduction of protective levels and the substitution G56D
produces a full lack of QnrA activity, the same modifications lead to a different scenario
in QnrS, in which the deletion of G56 results in a loss of Qnr activity, and the substitution
G56D was able to confer slight protection. Meanwhile, in QnrB, both modifications
inactivated Qnr (392). It is of note that G56 (QnrA and QnrS) or the equivalent amino
acid G53 (QnrB) is located in loop A (Table 7).
In fact, a series of studies attempted to determine the impact of substitutions on the
Qnr loops or on specific positions within pentapeptides. Along these lines, as men-
tioned above, the loss of loop A, loop B, or both loops has a negative effect on QnrB
activity. In addition, it has been proposed that amino acid substitutions for polar amino
acids in position i, or for amino acids with bulky side chains in position i⫹2 or i⫺2,
destabilize the right-handed quadrilateral ␤-helix structure, having a negative impact-
ing on Qnr activity (393, 394) (Tables 8 and 9).
The effect of amino acid changes on different levels of quinolone protection has also
been observed among different wild variants of Qnr belonging to the same family.
Thus, QnrVC7 confers lower levels of protection than QnrVC5 or QnrVC6 (394). This
finding has been related to the wild-type presence of A152 in QnrVC5 and QnrVC6.
QUINOLONE MODIFICATION
The first evidence of quinolone biodegradation was provided in the mid-1990s
when Martens and colleagues demonstrated the ability of some wood-rotting fungi to
degrade enrofloxacin (395). Further studies focused on the ability of Gloeophyllum
striatum to degrade enrofloxacin have proposed up to 4 possible degradation path-
ways, including oxidative decarboxylation, defluorination, hydroxylation at C-8, or
oxidation of the piperazinyl moiety (396), all showing different hydroxyl radical quin-
olone attack points (396). This model was thereafter expanded to other basidiomycetes,
including Cyathus stercoreus, a coprophilous fungus, and quinolones such as ciprofloxa-
cin (397). In addition, it showed the ability of other fungi (i.e., Xylaria longipes) to
transform danofloxacin into danofloxacin N-oxide, a metabolite with substantially less
antibacterial activity (398).
Further analyses of the ability of soil microorganisms to degrade quinolones suggest
the potential of different fungi (e.g., Candida spp.) and also of Mycobacterium spp. and
Pseudomonas spp. to fully degrade the danofloxacin piperazine ring (399). On the other
hand, the same study also described the ability of several microorganisms, including
Pseudomonas spp. and Mycobacterium spp., to metabolize danofloxacin to N-desmethyl
danofloxacin (399), a metabolite which retains antibacterial activity.
It is obvious that the intrinsic basal quinolone MIC is silently influenced in bacteria
that are able to inactivate or modify quinolones by any of these routes. Nonetheless, to
date, none of these mechanisms has been detected in a transferable genetic element.
AAC(6=)Ib-cr
In 2003, during a study focused on analyzing a series of plasmids carrying qnrA, a
few plasmids conferring unusually high levels of ciprofloxacin resistance (⬃4-fold
higher than usual) were detected (253). The authors suggested that differences in qnrA
expression levels might explain these differences but highlighted that the modulatory
effect on final qnr expression of unnoticed plasmid factors or the presence of unknown
TMQR might also be a reason (253). Further analyses resulted in the description of the
first bacterial enzyme able to selectively modify several fluoroquinolones, such as
ciprofloxacin and levofloxacin, increasing bacterial resistance levels (153, 170). Cur-
rently, this enzyme has been largely described in different microorganisms from various

TABLE 9 Effect of single amino acid substitutions at PRP units on Qnr protection levelsa
Change(s) in the indicated Qnr causing the indicated change in protection
QnrS1 QnrVC7
Position within TR QnrA1 (Neg) QnrB1 (Neg) QnrC1 (Neg) Neg Pos Neg Pos
i F13S
i F25A
i⫹2 T27I
i F30A
i⫺2 A36L/D
i L38P L35A L38R
i F40A
i⫺2 C43A
i F45A
i⫺2 S62D/G/L
i F66A
i⫺2 C72Y C69A/Y C72Y C72Y
i F76A
1⫺2 A82I/D/G/L/T
i⫺2 C92Y C89Y C92Y
i⫹2 G96D G93D G96D
i⫺2 A97Y
i F96A
i⫺2 A102D/G/L/T
i F101A
i⫺2 A114C/V A117C/V
i I116A
i⫺1 N120A
i L121A
i⫹2 Y123A
i⫺1 N125A
i⫺2 Q132D Q132L
i⫹1 E132A
i L136A
i⫺2 N139A
i⫹2 G148A
i⫺2 T152D/G/L T152A
i⫺1 S153P
i⫺2 S154A
i⫺1 D155A
i L159D L156A/D L159D
i⫹1 S157A
i⫺2 G159A
i F161A
i W166A
i⫺2 C172D/G C172L
i L176A
i L181A
i⫹1 D182Y D185Y
i⫺2 L184A
i⫹1 D188V
i⫹2 G193A
dm G209A
N27I ⴙ A91V ⴙ K195R
Q132L ⫹ T152A
T152A ⫹ C172L
F114Y ⫹ G196S
G7R ⫹ G98D
V6A ⫹ D95Y
aAmino acid substitutions are listed from top to bottom in the direction from the N to C termini. When more than one amino acid change is reported simultaneously,
they are placed at the bottom. Changes in the same row are analogous to each other. The amino acids highlighted in boldface type are those leading to a full loss
of Qnr activity and a subsequent lack of an effect on the final quinolone MICs. Note that cloning in different vectors may slightly affect the final full or partial loss of
activity. The amino acid change is reported only when there is a positive or negative effect of at least 4-fold on the MIC of quinolones described. Note that different
studies have determined the Qnr effects on different quinolones. No data obtained by IPTG induction have been considered because they represent the effect of
higher Qnr expression levels but not the intrinsic Qnr activity. TR, tandem repeat; dm, dimerization module; Neg, protective levels conferred by Qnr decrease; Pos,
protective levels conferred by Qnr increase (based on data from references 234, 235, 376, and 391–394).

environments, probably being the most common and frequent TMQR. In addition to its
presence in microorganisms from human samples, a recent report has shown a high
prevalence of AAC(6=)Ib-cr in animal and environmental samples (400).
The aac(6=)Ib-cr gene is frequently detected as a cassette of class 1 integrons or
associated with mobile elements such as IS26 (197, 245, 401, 402). Among these,
In37-like integrons of around 3.6 kb are largely detected in K. pneumoniae and have
disseminated to other bacterial species, including other Enterobacteriaceae and Aero-
monadaceae. In this integron, aac(6)-Ib-cr is placed in the first position, thereafter being
followed by three other gene cassettes: blaOXA-1, catB3, and arr3 (403–405). The
different In37 variants may in addition possess other antimicrobial resistance genes
after the first variable region, becoming complex integrons. Thus, the presence of qnrA1
or qnrB alleles (for instance, qnrB4 or qnrB10), which may also be linked to a blaDHA-1
gene, has also been reported in In37-like structures (245, 249, 253).
Differences have been observed in the final MICs conferred by AAC(6=)Ib-cr. Thus, in
addition to possible differences related to additional amino acid substitutions (see
below), upon analyzing 2 Klebsiella aerogenes (formerly Enterobacter aerogenes) isolates,
Ruiz et al. (402) showed differences in final ciprofloxacin MICs associated with differ-
ences in AAC(6=)Ib-cr expression levels. It was proposed that these differences were
related to the presence of a 12-bp deletion between IS26 and the initial ATG codon,
which displaces the ⫺10 box in one of the K. aerogenes isolates, leading to an almost
complete absence of expression of aac(6=)Ib-cr (402). It should be mentioned that the
AAC(6=)Ib-like enzymes have a great diversity in size (170, 406, 407); therefore, this text
follows the numeration provided by Robicsek et al. (170), but it should be noted that
other numerations may be considered in different reports (407, 408).
The originally described AAC(6=)Ib-cr protein [see “AAC(6=)Ib-cr subtypes,” below]
was reported as a protein of 172 amino acids in length belonging to the AAC(6=)Ib
group (253), but the initial ATG codon was corrected early on and was reported as a
protein of 199 amino acids in length. AAC(6=)Ib-cr is characterized by 2 amino-acid-
specific substitutions, W102R and D179Y, which are located in two external enzyme loops
(153, 407, 409). Furthermore, at the time of its description, it also presented its own
N-terminal region with 12 unique amino acids. Currently, this original enzyme is present
in GenBank as AAC(6=)Ib-cr5 (GenBank accession number WP_001749987). Subsequent
sequencing has shown the presence of several AAC(6=)Ib-cr variants with high heter-
ogeneity in size, mainly related to the enlarged N-terminal region [see “AAC(6=)Ib-cr
subtypes,” below]. The above-mentioned amino acid modifications confer to the
enzyme the ability to acetylate quinolones possessing an unsubstituted piperazinyl
group, such as ciprofloxacin and norfloxacin, but not other quinolones such as levo-
floxacin and moxifloxacin (153). In addition to the above-mentioned substrates, a later
study showed AAC(6=)Ib-cr (at least the original allelic variant described by Robicsek et
al.) activity over tosufloxacin (410). Mutagenesis analyses focused on both single amino
acid changes showed that when these are absent, the enzyme loses its ability to confer
quinolone resistance, while in the absence of W102R, D179Y also confers slight protec-
tion against quinolones but lower than that of wild-type AAC(6=)Ib-cr (153).
Similar to AAC(6=)Ib, acetyl coenzyme A acts as an acetyl donor (410), while a series
of differences regarding specific AAC(6=)Ib-cr substrates have been reported. Of these,
the most evident is a modest decrease [⬃10-fold with respect wild-type AAC(6=)Ib] in
the ability to acetylate kanamycin and the inability to acetylate neomycin B (410). In
fact, despite being characterized for its ability to acetylate some fluoroquinolones,
AAC(6=)Ib-cr acetylates kanamycin more efficiently (catalytic efficiency of kanamycin
acetylation ⬃50-fold higher than that of fluoroquinolones) (410). In addition, it is
interesting that the specific optimum substrate pHs for AAC(6=)Ib-cr also differ, being
6.1 to acetylate aminoglycosides and 7.7 to act on fluoroquinolones (410).
When AAC(6=)Ib-cr acts on aminoglycosides, the interactions are based on the
presence of numerous hydrogen-bonding interactions, while it has been suggested
that the interactions with quinolones are related to stacking interactions. In this sense,
the model of interaction between AAC(6=)Ib-cr and quinolones proposed by Vetting et

al. (410) considers that the amino nitrogen of the piperazinyl group located 2.7 Å from
Asp115 interacts with acetyl coenzyme A, playing a role as a proton acceptor during
catalysis. In this model, the quinolones establish stacking interactions with the ␤6/␤7
and ␣1=-␣2 loops of AAC(6=)Ib-cr (410). Within the ␣1=-␣2 loop, Trp49 directly interacts
with quinolones, and the Gly50-Ala54 region interacts with the pyridinone ring of the
quinolones through van der Waals forces. Tyr179 located on the ␤6/␤7 loop can interact
with the quinolone ring due to the establishment of attractive, noncovalent interac-
tions (␲-stacking interactions) of the p-orbitals of Tyr179 and quinolone rings. In this
model, Trp49 plays a relevant role in the stabilization of the structure. Meanwhile, Arg102
establishes interactions with Tyr179 leading to the stabilization of the optimal interac-
tion position of Tyr179 (410).
Maurice et al. (407) proposed an alternative interaction model. While this model
considered a similar role in stacking interactions for Tyr179, it proposed that Arg102
directly interacts with the keto or carboxy groups of fluoroquinolones through the
development of a hydrogen bond (407).
AAC(6=)Ib-cr subtypes. As mentioned above, 2 amino acid substitutions are suffi-
cient to confer a new ability to AAC(6=)Ib-cr. This is of special relevance because it
highlights the fact that small changes may modify the enzyme substrates. In this sense,
different AAC(6=)Ib-cr variants have been shown to confer quinolone resistance, or at
least this role has been strongly suggested (406, 409). Nonetheless, a series of studies
have not addressed this question and have mainly described the presence of
AAC(6=)Ib-cr by means of approaches such as specific PCR followed by restriction
fragment length polymorphism (RFLP) analysis (138, 411), while other studies report full
sequences presenting the 2 above-mentioned specific amino acids, as well as other
amino acid differences, even in the absence of specific studies to determine enzyme
activity. While these are valid approaches, they have the same limitations as any other
antibiotic resistance gene PCR detection method or new allele descriptions in the
absence of activity determinations. Indeed, a series of enzymes have been reported to
be able to confer quinolone resistance in the absence of definitive data.
On the other hand, different AAC(6=)Ib variants may possess the unnoticed ability to
confer slight resistance to specific quinolones. In this sense, many AAC(6=)Ib-cr se-
quences currently present in GenBank possess W102R and/or D179Y, differing mainly
in the N-terminal region or presenting a few amino acid differences. Therefore,
systematic cloning and evaluation of these enzymes could lead to a series of
relevant modifications in the current knowledge about this mechanism of quino-
lone resistance. In this sense, Kim et al. (406) detected a variant of AAC(6=)Ib-cr able
to acetylate gemifloxacin and zabofloxacin. This AAC(6=)Ib-cr variant was charac-
terized to present Y179 plus L117 (406), with both amino acids being present in the
enzyme described by Robicsek et al. (170) but lacking the amino acid change W102R
(406). Table 10 shows a series of AAC(6=)Ib-cr variants which have shown the ability
to acetylate quinolones.
Other Quinolone Modification Enzymes

The description of AAC(6=)Ib-cr demonstrates the possible effects of bacterial en-
zymes able to modify antimicrobial agents on quinolones. In this regard, a recent study
reported the presence of a plasmid-encoded phosphorylase able to inactivate cipro-
floxacin, called CrpP (154). This enzyme of 65 amino acids in length was detected in P.
aeruginosa, encoded within a conjugative plasmid (pUM505) of 123 kbp (154) belong-
ing to the IncI1 group, which was isolated in the early 1980s during a study designed
to determine the presence of resistance to heavy metals (412). Thereafter, in 2011, a
further analysis of this plasmid showed its ability to increase the MIC of ciprofloxacin in
P. aeruginosa, although no TMQR known at that time was detected, thereby suggesting
the presence of an unknown TMQR encoded within this plasmid (413). This finding was
confirmed in 2018 upon the identification of the crpP gene (154).
CrpP has 40% identity with an internal 42-amino-acid region of the aminoglycoside
phosphotransferase (APH) from Mycobacterium smegmatis and, despite not having the

TABLE 10 AAC(6=)Ib-cr variants with demonstrated quinolone-acetylating activitya

Size
GenBank accession no. IDb (no. of amino acids) Amino acid positionc Quinolone(s)d Reference
WP_001749987 cr5 199 M1 S2 N3 A4 K5 N20 R102 L117 Y179 D198 CIP, NOR, TSX 170
EUM72348 202 I Q H F Q D V CIP 406
—e ? ? ? ? ? ? G ? CIP 406
EUM72320 199 W CIP, GMX, ZBX 406
WP_015059932 cr4 225 T P G N D T CIP, NOR 409
aCIP, ciprofloxacin; GMX, gemifloxacin; NOR, norfloxacin; TSX, tosufloxacin; ZBX, zabofloxacin. Amino acids considered relevant for the acetylation of quinolones are
highlighted in boldface type. Note that possible enhanced or diminished activity as well as expanded or contracted substrate profile alterations might be related to
nonhighlighted amino acid differences. The absence of a specific quinolone does not preclude the inability of the enzyme to inactive it.
bIn the description present in GenBank, note that the first described AAC(6=)Ib-cr enzyme (170) is numbered “cr5.”
cFollowing the numeration provided by Robicsek et al. (170), note that the different sizes of acetylases may lead to different numeric positions in any variant. For
instance, the reported amino acid substitution “N20T” under GenBank accession number WP_015059932 is located in the equivalent position 46. When longer, amino
acid positions prior to M1 under GenBank accession number WP_001749987 have not been analyzed.
dQuinolones which might be acetylated.
eNo GenBank accession number is provided in the article by Kim et al. (406), and after a search in GenBank using the sequence under accession number
WP_001749987 and introducing a glycine in position 179, no concordant enzyme was found among the first 100 results.
catalytic APH enzyme motifs, presents Gly7 and Ile26, two conserved residues in APH
enzymes which are involved in catalysis and in ATP binding, respectively. Of note, the
concomitant presence of G7 and Ile26 was detected only in 63 of the ⬎1,000 closely
related (identity levels of ⱖ90%) amino acid sequences present in GenBank (see below)
(414). CrpP seems to be able to confer a slight increase in the MIC of ciprofloxacin (from
0.008 to 0.06 ␮g/ml) when cloned into pUC_20 and introduced into an E. coli J53
environment but had no effect on the remaining quinolones tested (levofloxacin,
moxifloxacin, nalidixic acid, and norfloxacin). Interestingly, upon comparing the effects
of CrpP when cloned into pUC_20 and when the native pUM505 plasmid was trans-
ferred to another P. aeruginosa isolate, the effect of the native plasmid was greater and
extended to norfloxacin and moxifloxacin, suggesting the presence of another un-
known quinolone resistance mechanism (154). Further analysis using the above-
mentioned quinolones as substrates showed that CrpP is able to phosphorylate nor-
floxacin but with an even lower efficiency than that of ciprofloxacin (with a Vmax/Km
ratio approximately 5-fold lower than that for ciprofloxacin) (154). Due to the novelty
of the CrpP description (to my knowledge, at the time of writing of this review, it has
been reported in only four articles), there is practically no knowledge of the extension of
this mechanism. Nonetheless, more than a thousand CrpP-like proteins grouped into more
than 37 different alleles, possessing one or a few amino acid changes, are present in
GenBank (414). Interestingly, all these sequences except for one uncharacterized 102-
amino-acid-long protein of A. baumannii (GenBank accession number SST11961) belong to
members of the Pseudomonadaceae (414). Most of these sequences were reported within
the P. aeruginosa genomic islands PAPI-1 and PAGI-5 (414), which are able to disseminate
through conjugation (415). These genomic islands have evolved from the ancestral conju-
gative plasmid pKLC102, which has been proposed to have an environmental origin (416).
These finding might suggest that the origin of CrpP is from plant-related bacterial com-
munities, perhaps belonging to the Pseudomonadaceae (414).
At the beginning of 2019, Chávez-Jacobo et al. (417) explored the presence of
crpP-like genes in 77 ESBL-carrying Enterobacteriaceae and in a historical collection of
66 E. coli J53-2 isolates containing plasmids transferred from ESBL-carrying clinical
isolates which were collected between 1988 and 2012. The authors detected 9 samples
(4 clinical isolates and 5 plasmids from the historical collection) carrying a series of
related crpP genes. Of these, the original sources were an E. coli isolate in 5 cases and
a K. pneumoniae isolate in the remaining 4 cases (417). Further analysis of 5 of these
plasmids (2 from E. coli and 3 from K. pneumoniae) showed that the first 2 encoded
products had protein identity levels ranging from 10.1% to 43.7% with original
CrpP, while the identity levels between the 3 CrpP-like proteins from K. pneumoniae
were higher, ranging between 57.1% and 65.7% (417). An analysis of the specific
effects of 3 of these CrpP-like proteins on the ciprofloxacin MICs showed increases

equivalent to those of the original CrpP protein (417). Nonetheless, neither data on
the presence of quinolone target selection nor those on the nalidixic acid MIC were
provided, allowing the possible selection of spontaneous mutants. In this sense, an
in silico analysis of these crpP-like sequences showed the presence of base inser-
tions/deletions that result in frameshifts (414). Pending further confirmation, cur-
rent data suggest the existence of a family of genes with the ability to slightly affect
the MICs of specific quinolones.
It should be taken into account that the authors proposed that a carboxyl group
present at position 3 of the ciprofloxacin molecule binds with ATP to be thereafter
phosphorylated and degraded (154). This radical is common to all quinolones (except
metioxate) (Fig. 3); therefore, it should be considered that CrpP may present activity
against untested quinolones, and as indicated above, the presence of CrpP modifica-
tions may lead to alterations of either expansion or constraint in the substrate pattern
as well as the final activity levels. In this sense, further antibiotic spectrum determina-
tion of detected CrpP variants will be of relevance.
TRANSFERABLE EFFLUX PUMPS

Although transferable oqxAB genes were first described in 2004 (156), the ability of
transferable efflux pumps to extrude quinolones from bacteria to the environment was
demonstrated in 2007 (157–159).
Most of the studies in the field are focused on the detection of 2 different efflux
pump groups (QepA and OqxAB). In addition, other scarcely characterized efflux pumps
such as QacA and QacB or those encoded within the plasmid pRSB101 are also able to
pump out quinolones from bacteria.
OqxAB
In 2003, Sørensen et al. (155) were the first to describe the presence of a plasmid
(pOLA52)-borne mechanism of olaquindox resistance in E. coli isolated from swine.
Further studies to determine the exact mechanism of olaquindox resistance encoded
within pOLA52 showed its efflux pump nature, detecting 2 ORFs, encoding a 391- and
a 1,050-amino-acid-long protein, which were named OqxA and OqxB (here, these 2
specific alleles are referred to as OqxA1 and OqxB1). OqxA and OqxB present a certain
degree of identity, especially at the amino acid level, with inner membrane (OqxA) and
periplasmic (OqxB) components of previously described RND efflux pumps, such as
MexEF of Xanthomonas axonopodis, MexXY of P. aeruginosa, and AcrAB of E. coli (156).
The RND efflux pumps need a third component to be active, that is, an outer membrane
protein (OMP). Hansen et al. (156) showed that in an E. coli genetic background, TolC
plays this role, and therefore, TolC-like proteins presumably play this role in other
Enterobacteriaceae. Nonetheless, the role of OqxAB as a quinolone resistance mecha-
nism was not established until 2007, when its ability to extrude different quinolones,
such as nalidixic acid, ciprofloxacin, and norfloxacin, together with a series of unrelated
antibacterial agents and toxins was observed (157). Similar to what has been described
for other RND efflux pumps, such as AcrAB-like efflux pumps in Enterobacteriaceae or
MexAB-like efflux pumps in Pseudomonadaceae (239, 418, 419), it has been suggested
that Phe-Arg-␤-naphtylamide may inhibit OqxAB (420).
Further studies aimed at characterizing pOLA52 showed a plasmid size of 51,602 bp,
classified as belonging to the IncX1 incompatibility group (200). Norman et al. (200) also
showed that together with a putative regulator gene (later proposing the name OqxR),
OqxAB proteins were flanked by IS26, thus being a composite transposon, demonstrat-
ing the presence of 100% (oqxA) and 99% (oqxB) identities with the components of a
K. pneumoniae putative efflux pump, which was thereafter considered the OqxAB
original bacterial source (199–201). Posterior analyses of the role of OqxR have shown
that it may be involved in the downregulation of OqxAB expression levels. Thus, upon
analyzing the expression levels of K. pneumoniae chromosomal oqxA and oqxB genes,
it was shown that the presence of the specific OqxR amino acid changes reported

below correlates with higher levels of expression of these genes, which revert when a
plasmid carrying wild-type OqxR is used to complement the bacteria (421, 422):
● F6S
● V102G
● Q11L, D95E, and V113I
● N38T, D95E, V113I, and H159L
● Δ73–77
● Δ88 –94
where Δ indicates a deletion. An association between these mutations and the final
levels of OqxAB expression has been proposed (421, 422). Note that when there is
more than one amino acid change, the presence of simple polymorphisms needs to
be considered. To my knowledge, there is no study on the role of OqxR in
transferable oqxAB expression levels. Nonetheless, transferable oqxAB regulation
mediated by chromosomal regulatory genes such as ramA and rarA has been shown
in S. Typhimurium (201, 420). This finding correlates with the final MICs of the
antibacterial agents tested. Therefore, the specific chromosomal genetic back-
ground plays a crucial role in the final levels of expression of oqxAB and, subse-
quently, in its contribution to the final antimicrobial resistance levels. This finding
can likely be extrapolated to other TMQR.
Although the presence of differences in the sequence of K. pneumoniae chromo-
some-encoded OqxAB has been described (tens of different chromosomal OqxA and
OqxB alleles are recorded in GenBank), most of the studies on transferable OqxAB
address only the presence/absence of OqxAB. In 2012, the presence of new transferable
allelic variants of OqxA and OqxB were described, differing in 1 or 2 amino acids from
the original OqxA and OqxB (thereafter named OqxA1 and OqxB1, respectively) (177).
Furthermore, an in silico analysis of the presence of new transferable OqxA/OqxB
variants in GenBank showed the presence of at least 14 new OqxA and 28 OqxB
previously unnoticed variants, which had clearly evolved from K. pneumoniae chromo-
somal OqxAB, as well as the dissemination of these variants through a series of
microorganisms (Tables 11 and 12). While most of these alterations are probably
polymorphisms that do not affect the final OqxAB activities, the possible involvement
of activity levels and/or the expansion/contraction of substrate profiles cannot be ruled
out. In any case, the effect of these modifications on the final activity of OqxAB remains
to be elucidated. Interestingly, K. pneumoniae is not the only member of the Entero-
bacteriaceae carrying an OqxAB-like efflux pump. Closely related efflux pumps have
been described as being indigenous to other microorganisms such as other Klebsiella
spp. or Enterobacter spp. (201). In this regard, the above-mentioned analysis also
showed the presence in GenBank of an E. coli genome (strain TUM18641; GenBank
accession number NZ_BGTY01000006) carrying OqxA (GenBank accession number
WP_087857967) and OqxB (GenBank accession number WP_113374178) with 30 and 29
amino acid differences from OqxA1 and OqxB1, respectively, but closely related to
OqxAB of K. aerogenes; thus, OqxA presents a maximum identity of 100% with that of
K. aerogenes strain CRK0055 (GenBank accession number RNT35078), and OqxB, with
only 2 amino acid differences, presents an identity of 99.8% with OqxB of K. aerogenes
strains AR_0431 and GN04835 (GenBank accession number WP_047066491). Therefore,
the unnoticed dissemination of another variant of OqxAB with an undefined effect on
quinolones (or other antibiotic agents) has been suggested. This finding, especially if
this new OqxAB-like protein expands to other E. coli isolates or other microorganisms,
opens the door to suggesting an alternative name for this new variant, as occurred with
QnrE.
Internal partial genomic integrations or recombinations of transferable genetic
structures leading to the full or partial loss of oqxA or oqxB may explain the studies in
which only one of these genes is detected in nonindigenous microorganisms (341, 423).

Ruiz
TABLE 11 Amino acid changes described in transferable OqxAa

GenBank accession no.b
Yrc DNA Amino acid % identityd Amino acid difference Gram-negative genus or generae Referencef
2007 EU370913g AAP43109 100.0 G8 G16 M19 S30 A113 R116 I159 S183 A199 Q244 R338 D339 ins Enterobacter, Escherichia, Salmonella, Shigella 156
2012 NG_050420 WP_063865358 99.7 V Escherichia, Raoultella, Salmonella, Enterococcus 177
2016 NZ_LVMD01000084 WP_063501637 99.7 S Escherichia
2016 KT727030 AMW92379 99.7 R Enterococcus
2018 CP029215 AWJ07841 99.7 E Escherichia
2018 CP026492 AUY47426 99.7 I Escherichia
2018 KT716392 AMW92376 99.7 H Enterococcus

2016 FLWH01000008 SBY67709 99.5 E V Escherichia
2017 NZ_MKFO01000039 WP_089069082 99.5 E V Escherichia
2017 MOGH01000057 OJM31094 99.5 V R Escherichia 56
2018 JAMW01000061 OXY63391 99.5 K V Salmonella
2018 MG028668 AWG41968 99.5 V T Enterobacter
2018 MG028669 AWG41969 99.5 V C Enterobacter
2018 PTMN01000089 PPW02434 99.2 41PAP Escherichia
aGram-positive microorganisms are highlighted in boldface type. No allelic numeration has been included to avoid confusion with a series of K. pneumoniae chromosomal OqxA proteins that are present in GenBank with
an assigned allelic numeration. Note that these variants may be present in other genera and that other OqxA variants may remain undetected. ins, insertion.
bIn several cases, multiple valid DNA/amino acid sequences may be found in GenBank.
cDate of first published report. If no published report has been found, the data for the older GenBank record are reported.
dThe minimum degree of identity considered was 99%. A series of OqxAB efflux pumps with lower levels of identity are present in GenBank, including a transferable oqxAB gene probably derived from an ancestral
K. aerogenes isolate (GenBank accession number NZ_BGTY01000006) (see “OqxAB”).

eIn all cases, it is considered that any OqxA reported in a microorganism other than Klebsiella spp. belongs to a transferable gene, irrespective of chromosomal/plasmid location or the absence of specific genetic
environment data. The presence of transferable OqxA in Klebsiella spp. is not reported here.
fFirst published report.
gFirst OqxA described as a transferable determinant.
cmr.asm.org 40
TABLE 12 Amino acid changes described in transferable OqxBa
GenBank accession no.b Gram-negative
% genus or
Yrc DNA Amino acid identityd Amino acid difference generae Referencef
2007 EU370913g WP_000347934 100.0 P102 L138 G148 V217 M313 Q325 A432 L284 H434 G463 A493 G540 G544 G547 A551 V612 V645 A650 L672 A699 Q778 D749 Y783 E788 Q799 V839 T1050 ins Enterobacter, 156
Escherichia,
Salmonella,
Shigella
2012 JF912901 AEM45928 99.9 I Escherichia 177
2017 KX518744 APO16513 99.9 I Escherichia 468
2018 NZ_NRYU01000105 WP_113449358 99.9 L Escherichia
2018 NZ_PJHN01000068 WP_112910686 99.9 Q Escherichia 469
2018 NZ_PJGF01000097 WP_112889165 99.9 K Escherichia 469
2017 MOIC01000152 OJO61665 99.9 E Escherichia 470
2016 FLWH01000008 SBY67683 99.9 N Escherichia
2018 NZ_NRXP01000002 WP_113402128 99.9 S Escherichia

2018 NZ_PQHV01000042 WP_105906775 99.9 E Escherichia
Transferable Mechanisms of Quinolone Resistance
2018 KT716391 AMW92372 99.9 Y Escherichia, 169

Salmonella,
Enterococcus
2017 NZ_NGVB01000050 WP_087525850 99.9 F Escherichia
2017 NZ_FZIQ01000054 WP_096216538 99.9 L Escherichia
2012 JF912902 AEM45930 99.8 Y I Escherichia, 177
Raoultella,
Salmonella
2018 PTNE01000065 PPW37064 99.8 Q E Escherichia
2016 KT334335 ALI92905 99.8 H Q Salmonella
2016 KT727030 AMW92380 99.8 L Y Enterococcus
2016 NZ_KQ089493 WP_048299610 99.8 N E Escherichia
2016 MOIX01000077 OJP65617 99.8 E E Escherichia
2018 NZ_NSAZ01000061 WP_113455638 99.8 Y E Escherichia 469
2015 KF414089 AGZ20250 99.7 Y I I Escherichia 212
2016 AGZ20250 AMW92377 99.7 Y S E Enterococcus
2018 PTML01000068 PPX08745 99.7 411XVD Escherichia
2018 PTML01000068 PPV65433 99.6 411XVVD Escherichia
2015 KF414080 AGZ20241 99.6 N S E F Escherichia 212
2016 LUIP01000142 KYE44549 99.5 K S R E N Salmonella
2011 FN811184 CBL62366 99.5 K S S R E Salmonella
2018 NZ_BGKO01000006 WP_109956222 99.3 N K S V G F I Escherichia
aGram-positive microorganisms are highlighted in boldface type. No allelic numeration has been included to avoid confusion with a series of K. pneumoniae chromosomal OqxB proteins which are present in GenBank with
an assigned allelic numeration. Note that these variants may be present in other genera and that other OqxB variants may remain undetected. ins, insertion.
bIn several cases, multiple valid DNA/amino acid sequences may be found in GenBank.
cDate of the first published report. If no published report has been found, the data for the older GenBank record are reported.
dThe minimum degree of identity considered was 99%. A series of OqxAB efflux pumps with lower levels of identity are present in GenBank, including a transferable oqxAB gene probably derived from an ancestral K.
aerogenes isolate (GenBank accession number NZ_BGTY01000006) (see “OqxAB”).

eIn all cases, it is considered that any OqxB reported in a microorganism other than Klebsiella spp. belongs to a transferable gene, irrespective of chromosomal/plasmid location or the absence of specific genetic
environment data. The presence of transferable OqxB in Klebsiella spp. is not reported here.
fFirst published report.
gFirst OqxB described as a transferable determinant.
cmr.asm.org 41
In addition, the presence of transferable OqxAB not derived from the K. pneumoniae
genome may also contribute to explaining this phenomenon.
Initial studies were developed using samples of veterinary origin and thereafter in
animal-exposed human populations (e.g., farmworkers), suggesting a relevant role of
livestock management in the selection and spread of OqxAB-carrying isolates (155,
230). Nonetheless, despite the relevance of the farm environment, transferable OqxAB
proteins have currently also been described in samples from healthy and sick people as
well as from food samples, wild animals, and environmental samples (202, 424–426).
Furthermore, the range of plasmids in which oqxAB has been reported has expanded,
including plasmids classified within the IncF or IncHI2 group, among others (354, 425,
427).
In 2018, the presence of OqxAB in Gram-positive microorganisms was first reported.
A study performed in China showed the presence of this efflux pump in E. faecalis in a
genetic structure flanked by IS26 and linked to an incomplete aph(3=)-IIa gene (169).
Interestingly, these samples were from a pig farm.
QepA
To date, 4 QepA variants have been described in the literature. The first qepA gene
was described at almost the same time by 2 independent French and Japanese groups
in 2007 (158, 159). A new QepA variant, QepA2, differing in 2 amino acid codons, was
described in 2008 (178). Finally, QepA3 and QepA4 were described in 2015 and 2017,
respectively (428–430). Nonetheless, an analysis of GenBank records showed that at
least 6 other new complete qepA genes have been fully sequenced as well as the
presence of additional partial QepA sequences exhibiting their own specific amino acid
codon changes (179). All 6 uncharacterized QepA proteins were detected in members
of the Enterobacteriaceae, thereby being acquired from an external source, irrespective
of their exact genetic environment (chromosome or plasmid) (179). Similar to Qnr (and,
in fact, with a long series of genes), a centralized QepA repository is needed to bring
order to the nomenclature.
Similar to other TMQR, the mobilization of qepA has been related to the presence of
different insertion sequences, such as IS26 and ISCR3C (158, 175, 430). The qepA4 gene
has been detected in an atypical class 1 integron preceded by a defective dfrB4 gene
and followed by an ISCR3 element (428).
QepA is a proton-dependent efflux pump which varies in size, presenting 14
transmembrane segments (14-TMS) which belong to the major facilitator super-
family (MFS) (159). An extrusion product pattern has been established in QepA1 and
QepA2, including more-hydrophilic quinolones such as ciprofloxacin and norfloxa-
cin but with a marginal or null ability to extrude hydrophobic quinolones such as
ofloxacin levofloxacin, moxifloxacin, and nalidixic acid (159, 178, 431). Furthermore,
these variants are unable to pump out nonquinolone agents such as erythromycin,
chloramphenicol, rifampin, and tetracycline (159, 178). No data on pumping sub-
strates of the remaining QepA variants are available. In this regard, it should be
mentioned that despite having identities of ⱖ90% among the 10 QepA variants,
these slight differences include insertions and deletions (179). Thus, while the 4
reported QepA variants have 511 amino acids, a deletion of 5 amino acids
(Δ432SAALP), just after the 13th transmembrane section, and an insertion of 2 amino
acids (Ins357LG) within the 11th transmembrane transept have been detected in
QepA GenBank records (179). These insertions and deletions may affect the final
QepA structure and may therefore have a major impact on either the expansion or
the restriction of efflux pump substrate profiles as well as on substrate affinities,
which may lead to different efficiencies of pumping out, with a direct impact on the
final effect on antimicrobial resistance levels.
The first phylogenetic analysis proposed that the origin of QepA was within the
Actinomycetales order (158). Furthermore, a possible ancestor within the actinomycetes
also agrees with the G⫹C content of QepA (⬃72%) (158). Nonetheless, the addition of
new genomic data in GenBank has shown that the higher levels of identity with the

currently described or putative Actinomycetales efflux pumps are ⬃40%, while the
identities of QepA with a series of 512 putative efflux pumps of the Comamonadaceae
family (i.e., Pseudorhodoferax spp.) reach values of ⬃80%. Despite the scarce data in this
respect, the G⫹C content of the Pseudorhodoferax genus has been reported to be ⬃68
to 70%, thereby agreeing with that of QepA. These findings suggested the possibility
of an alternative origin within the Comamonadaceae family (179). In agreement with
this alternative origin of QepA, in a study by Yamane et al., the chromosomal efflux
pump with higher levels of identity with QepA1 in fact belonged to a member of the
Comamonadaceae (i.e., Polaromonas spp.) (158).
QacA and QacB

Although described in the 1980s (180), the ability of the MFS 14-TMS proton-
dependent efflux pumps QacA and QacBIII (an allelic variant of QacB) to extrude
quinolones from bacteria was established only in 2010 (166).
The Qac determinants are mechanisms of resistance to antiseptic and disinfec-
tant monovalent and divalent cations and are widely disseminated in S. aureus
(432). Thus, in a study designed to analyze the variability of Qac determinants, an
allelic variant of QacB, named QacBIII, was observed, possessing 4 amino acid
differences from the originally described QacB (I26V, I167L, A184V, and A320E). Of
these, the presence of E320 in transmembrane segment 10 was directly related to
4-fold increases in the MICs of norfloxacin and ciprofloxacin when cloned into S.
aureus RDN1 within pTZN10; further in vitro introduction of A320 in QacBIII returned
the MICs to parental levels (166). In the same study, it was observed that upon
cloning QacA, the MICs of ciprofloxacin and norfloxacin increased slightly (2-fold),
which was suggested to be related to the presence of aspartic acid at position 323
(166). Interestingly, D332 has also been related to the increased activity of QacA over
divalent cations (433). This study showed a high prevalence of QacBIII (20 isolates,
representing 80% of the isolates analyzed). Nonetheless, a recent study in Japan
showed a slight decrease in the prevalence of QacBIII in methicillin-resistant S.
aureus (MRSA) isolates from the period from 2010 to 2011 to the period from 2014
to 2015 (13.3% to 5.5%) (434). Furthermore, the authors highlighted that 80.7% of
QacBIII-positive isolates belonged to staphylococcal cassette chromosome mec
(SCCmec) type II; of these, the multilocus sequence typing (MLST) pattern was
established in eight cases, with all belonging to sequence type 764 (ST764) (434).
Another study in Spain of 159 S. aureus clinical isolates failed to detect the QacBIII
variant (in fact, they detected only 1 isolate carrying QacB) (435). The diversity in the
prevalence of QacB might reflect local differences and suggests the need to expand
the studies on the presence of QacBIII to new geographical areas. Unfortunately, no
other article related to the presence of QacBIII or about the role of QacBIII (or other
QacA/B variants) has been found.
Other Transferable Efflux Pumps

A series of usually unconsidered efflux pumps with the ability or the potential to
extrude quinolones from bacteria has been described.
Thus, among other plasmids recovered from a wastewater treatment plant bacterial
community, Szczepanowski et al. characterized a plasmid called pRSB101 (436). This
plasmid of 47,829 bp does not fit within any described incompatibility group. pRSB101
carries different antibiotic resistance determinants, including a mixed-type tripartite
multidrug efflux pump. When cloned into E. coli, increases from 80 to 550 ␮g/ml and
from 0.5 to 1.25 ␮g/ml were observed for the MICs of nalidixic acid and norfloxacin,
respectively (436).
This efflux pump possesses 2 components belonging to the RND family. These
components include a TetR/AcrR family transcriptional regulator showing 40% identity
with a putative regulator of Geobacter sulfurreducens (GenBank accession number
NP_952005). Downstream from this regulator gene, an RND membrane fusion protein
is encoded, possessing 45% identity with that of G. sulfurreducens (GenBank accession

number NP_952003). These components are followed by a permease and by an ATPase

(probably involved in providing energy for active transportation through ATP hydro-
lysis) belonging to the ATP-binding cassette (ABC) efflux pump family, also showing a
high degree of identity (59% and 45%, respectively) with components of the same
efflux system of G. sulfurreducens. No OMP-encoding gene was present in pRSB101, and
therefore, the authors proposed that the system required a chromosomally encoded
OMP to be functional (436).
The role of other plasmid-encoded efflux pumps in the development of quinolone
resistance remains to be elucidated. For instance, in 2013, a MexAB-OprD-like efflux
pump was described, located within 2 IS1 elements within an IncH1 plasmid (pNDM-
CIT) from a multidrug-resistant C. freundii isolate for which no further data are available
(437).
TMQR AND THE FUTURE

Antibiotic resistance mechanisms are as old as antibiotic production (438) and
may be traced back to ancient samples from hundreds or thousands of years ago
(439, 440). In some cases, these mechanisms have been related to adaptative
mechanisms of antibiotic producer microorganisms to avoid self-killing or of other
neighboring microorganisms to increase survival (441–444). Other mechanisms,
such as TMQR, are recent adaptative functions of ancient molecules, possessing
another original physiological function, in response to the presence of new non-
natural toxic agents related to human action, such as quinolones, a fully synthetic
antibacterial agent family.
The first scientific studies on antibacterial agents date from the mid- to late 19th
century (445–448), and the introduction of antibacterial agents into clinical practice to
fight infectious diseases dates from the late 19th century and the early 1900s (449, 450).
Nonetheless, the effect of these items on the ecology of bacteria was minimal if any.
However, the changes in the microbial world induced by the pressure exerted after the
clinical introduction of the current antibacterial agents in the 1930s (451) became
exorbitant and absolutely immeasurable. The success of penicillin and subsequent
antibiotics against infectious microorganisms led to an imbalance in the bacterial
population, favoring the selection of microorganisms possessing antibiotic resistance
mechanisms (Fig. 9).
TMQR have evolved from a series of genes with an as-yet-unknown physiological
function, with their unexpected effect on the final MICs of quinolones benefitting
their spread outside their original environment to the whole world. In this scenario,
and fueled by the direct, continuous growth selection pressure exerted by quino-
lones in human, veterinary, and environment settings, further steps in the history of
TMQR will include their installation in new genetic structures and their spread to
new microorganisms, including a greater presence in Gram-positive microorgan-
isms, as has recently been described (167–169). More efficient variants that are able
to expand or modify their quinolone affinity or to confer higher levels of quinolone
resistance will be selected. The description of new transferable Qnr families derived
from new chromosomal Qnr ancestors is also foreseen, including derivatives from
chromosomal Qnr of Gram-positive microorganisms. Thus, the incessant continuous
description of new variants of the currently established TMQR, such as Qnr, QepA,
AAC(6=)Ib-cr, and OqxAB, will advance in the future. Furthermore, a dribble of TMQR
belonging to new families, such as the recently described CrpP (154), will also
probably be described. In this sense, the potential of amino acid changes in the
current antibiotic-modifying enzymes (or in other physiological acetylases or phos-
phorylases or other enzymes able to modify molecules) is a fertile and practically
unexplored field.
CONCLUSION
Within a little over 20 years, TMQR have evolved from being a scientific, almost
undetectable rarity to a worldwide epidemic. This finding has been made possible by

FIG 9 Selection of antibiotic resistance. (A) In the preantibiotic era, the presence of antibiotic-resistant
microorganisms was rare. The introduction of antibiotics led to killing of antibiotic-susceptible bacterial
populations; the selection of the minority antibiotic-resistant populations, which were present in the
preantibiotic era; the dispersion of plasmid-encoded mechanisms of resistance; as well as the generation
of new resistant strains (by selecting chromosomal mutations). This phenomenon led to the current high
levels of antibiotic resistance. (B) Antibiotic resistance may be stable, with a minimal or null effect on bacterial
fitness, thus being easily fixed in the bacterial population. The antibiotic-resistant microorganisms tend to be
present even in the absence of antibiotic pressure. Antibiotic resistance may also be unstable, affecting
bacterial fitness; the absence of antibiotic pressure tends to dilute in the general bacterial population.
Nonetheless, antibiotic resistance may act in an indirect manner by other antibacterial agents favoring the
fixing of genetic structures carrying multiple mechanisms of antibiotic resistance. Compensatory mutations
are mutations which have no direct effect on antibiotic resistance but lead to the recovery of lost fitness.
When selected, the microorganisms act as those with stable resistance.
human attitudes. Thus, quinolone use, similar to that of all antibacterial agents, has
become one of absolute overuse and misuse; that is, the use of quinolones has
expanded beyond the treatment of bacterial infectious diseases to a series of unnec-
essary roles, such as livestock growth promotion. This, in addition to the high levels of
use in veterinary settings as a prophylactic agent, the uncontrolled access to antibac-
terial agents in a long series of countries, the high rate of misprescription, self-
medication, erroneous posology, and early treatment discontinuation, has led to the
current scenario of quinolone resistance that, as with all other antibacterial agents, has
squandered the treasure that antimicrobials are.
The direct, continuous, and growing selection pressure exerted by antibiotics in
human and microbiota commensal members and pathogenic microorganisms is inces-
sant, favoring the survival of microorganisms which carry antibiotic resistance deter-
minants such as Qnr or other TMQR. These microorganisms that possess adequate
antibiotic resistance genes are the winners of the race involving the survival of bacteria
in the antibiotic era (Fig. 9).
It is undeniable that TMQR will remain with us. At present, not even the strictest
antibiotic control policies will return the presence of TMQR determinants to the level of
the prequinolone era, but these measures are necessary to control and limit their
continuous spread.
ACKNOWLEDGMENTS
This research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors.
I thank Donna Pringle for language correction.

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Joaquim Ruiz, M.S.C., Ph.D., is a microbiolo-

gist who graduated from the Science Faculty
of the Universitat Autònoma de Barcelona.
He has developed his scientific career at the
Hospital Clinic of Barcelona, being Associate
Research Professor at the Barcelona Institute
for Global Health and Visiting Lecturer at the
Universidad Peruana Cayetano Heredia in
Lima, Peru. At present, he is an External Re-
searcher at the Universidad Continental in
Lima, Peru. He has worked in the area of
antibiotic resistance, being especially interested in the study of quino-
lone resistance mechanisms and spread since 1993. In recent years, he
has focused his research on the knowledge of the dynamics of the
development of antibiotic resistance and dissemination in different
environments and on the study of infectious diseases in low- and
middle-income countries, mainly diarrheagenic and bacteremic patho-
gens affecting children. Since 2008, he has also been leading a research
line devoted to the understanding and knowledge of Carrion’s disease.
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Transferable Mechanisms of Quinolone Resistance from 1998 Onward

Article in Clinical Microbiology Reviews · August 2019

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Transferable Mechanisms of Quinolone Resistance from 1998

Citation Ruiz J. 2019. Transferable mechanisms

October 2019 Volume 32 Issue 4 e00007-19 Clinical Microbiology Reviews cmr.asm.org 1

sion of TMQR descriptions, which deﬁnitively changed the epidemiology of quino-

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 2

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 3

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 4

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TABLE 1 General classiﬁcation of the main quinolonesa

Pyridopyrimidines Piromidic acid

Quinolines Droxacin Amifloxacin Balofloxacin Antofloxacin Nemonoxacin

.gov/search/#query⫽Metioxate). Nonetheless, it is usually classiﬁed as a ﬁrst-generation quinolone.

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 6

Evolution of Quinolone Resistance over Time

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TABLE 2 Quinolone-related severe adverse eventsa

able to cause similar effects in speciﬁc cases or circumstances.

microorganisms, such as Campylobacter spp., presented extremely high percentages of

Quinolone Resistance Mechanisms

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 8

quinolones, which modify the bactericidal action of quinolones to a bacteriostatic

GENERAL OVERVIEW OF TMQR

Nomenclature of the Transferable Mechanisms of Quinolone Resistance

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 9

aimed at determining the presence of olaquindox resistance mechanisms (155, 156).

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Changing Resistance Paradigms

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 11

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Nonetheless, this phenotype may be mediated by the concomitant presence of TMQR

Clinical Relevance of TMQR

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TABLE 3 Essential data on TMQR

Effect on quinolone MIC

Furthermore, the presence of decreased susceptibility to quinolones has also been

October 2019 Volume 32 Issue 4 e00007-19 cmr.asm.org 14

October 2019 Volume 32 Issue 4 e00007-19

Antibiotic resistance determinantsb

October 2019 Volume 32 Issue 4 e00007-19

eAlso reported as bla

tnpA within In640 [aac(6=)Ib-cr-blaOXA-1-arr3-dfrA27⌬-aadA16⌬-qacE⌬1].

lThe aac(6=)Ib-cr gene is harbored within a class 1 integron {In1231 [aac(6=)Ib-cr-arr3]}.

eukaryotic cells has precluded its clinical use (467).

lipopolysaccharide (LPS) biosynthesis, which were correlated with a parallel increase in

Molecular Epidemiology of TMQR

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TABLE 5 Overall view of TMQRa

Efﬂux system QepA 10 10 511m 2007 Comamonadaceae

Antibiotic modiﬁcation AAC(6=)Ib-cr ⬎5 7 2006 Y

Slow growth pKM101

hEstablished or proposed original chromosomal sources.

transferability has not been demonstrated (331).

oKlebsiella pneumoniae and Klebsiella aerogenes (see “OqxAB”).

the chromosomes of different Gram-negative microorganisms, mostly related to water