MINIREVIEW

Therapeutics and Prevention

Combined Antifungal Resistance and Biofilm Tolerance: the

Global Threat of Candida auris
Ryan Kean,a Gordon Ramageb

a
Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
b Oral Sciences Research Group, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United
Kingdom

ABSTRACT The enigmatic yeast Candida auris has emerged over the last decade
and rapidly penetrated our consciousness. The global threat from this multidrug-
resistant yeast has generated a call to arms from within the medical mycology com-
munity. Over the past decade, our understanding of how this yeast has spread glob-
ally, its clinical importance, and how it tolerates and resists antifungal agents has
expanded. This review highlights the clinical importance of antifungal resistance in
C. auris and explores our current understanding of the mechanisms associated with
azole, polyene, and echinocandin resistance. We also discuss the impact of pheno-
typic tolerance, with particular emphasis on biofilm-mediated resistance, and present
new pipelines of antifungal drugs that promise new hope in the management of C.
auris infection.

KEYWORDS Candida, antifungal resistance, biofilms, tolerance

T he emergence of new microbial pathogens combined with escalating rates of

antimicrobial resistance (AMR) continue to pose a global threat. The field of medical
mycology is acutely aware of this since the emergence of the pathogenic yeast Candida
auris, a member of the Metschnikowiaceae family. In the decade since its discovery in
2009 (1), it has quickly emerged as a prolific nosocomial pathogen, causing infections
across all inhabited continents. A retrospective review of strain collections suggests
that it first appeared in South Korea in 1996 (2). The simultaneous and unprecedented
emergence of genetically distinct clades of the species has mystified the scientific and
medical mycology communities. C. auris possesses the “superbug”-like traits typically
associated with common hospital-acquired infections, such as methicillin-resistant
Staphylococcus aureus (MRSA), in that it can often be multidrug resistant (MDR) and can
survive and persist in the nosocomial environment. To exacerbate matters, unambig-
uous identification of this yeast remains difficult, further emphasizing the organism as
a global health threat.
At the writing of this article (June 2019), C. auris had been reported in 33 countries Citation Kean R, Ramage G. 2019. Combined
antifungal resistance and biofilm tolerance:
on 6 different continents. Crude mortality rates are varied but have been reported to the global threat of Candida auris. mSphere
be as high as 66% (3). Whole-genome sequencing has revealed four geographically and 4:e00458-19. https://doi.org/10.1128/mSphere
phylogenetically distinct clades of the organism (South American, African, South Asian, .00458-19.
Editor Aaron P. Mitchell, Carnegie Mellon
and East Asian), which contain almost genetically identical strains within clades but can
University
harbor tens of thousands of single nucleotide polymorphism (SNP) differences between Copyright © 2019 Kean and Ramage. This is an
clades (4). Interestingly, every clade, with the exception of the East Asian clade, has open-access article distributed under the terms
been associated with outbreaks and invasive infections. In a recent study of isolates of the Creative Commons Attribution 4.0
International license.
from South Korea, cases associated with the East Asian clade are almost uniquely
Address correspondence to Gordon Ramage,
(⬎93%) associated with ear infections (2). The enigma of the origin and evolution of C. gordon.ramage@glasgow.ac.uk.
auris is perplexing and not currently known. Casadevall and colleagues recently pro- Published 31 July 2019
posed an interesting and controversial hypothesis that the emergence of C. auris could

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FIG 1 Geographic antifungal resistance rates of Candida auris. Heatmap depicts the percentage of
resistant isolates to fluconazole (FLU), amphotericin B (AMB), and echinocandins (ECH), and numeric
values of resistance are given in Table S1. *, the echinocandin is anidulafungin and not caspofungin; #,
the echinocandin is micafungin; a, includes isolates from other countries; b, isolates from Pakistan, India,
South Africa, and Venezuela.

potentially be the first example of a fungal pathogen to emerge as a consequence of

climate change (5). The authors postulate that based on their phylogenetic and
thermotolerance analysis of C. auris, the increase in ambient temperatures as a result of
global warming may have acclimatized the organism to adapt to and survive at avian
and mammalian temperatures, with transmission from birds to rural areas being a
potential mechanism of its emergence. However, this is highly speculative, and it is
likely that many other factors are involved, which warrants further study.
The principal factor that makes this organism so enigmatic is its intrinsic resistance
to conventional front-line antifungal agents and its tolerance to antiseptics and disin-
fectants. Its resilience and adaptivity within a variety of clinical environments have
afforded it with the opportunity to emerge and cause alarm among medical professions
worldwide. This review will focus on exploring the factors driving its resistance to
therapeutic management that we have uncovered over the first decade of its discovery.

ANTIFUNGAL RESISTANCE: FROM CLINIC TO LABORATORY

According to a recent review by Lockhart, when it comes to C. auris, resistance is the
new norm (6), with a significant minority of clinical isolates displaying antifungal
susceptibility. Resistance has been reported across all main classes of antifungals, with
a worryingly high proportion of isolates being documented as multidrug resistant. No
definitive MIC breakpoints exist, but tentative breakpoints have been suggested by the
Centers for Disease Control and Prevention (https://www.cdc.gov/fungal/candida-auris/
c-auris-antifungal.html) and are supported by studies in a neutropenic mouse model to
assess antifungal target ranges (7). Using these guidelines, the rates of resistance to
fluconazole (FLU), amphotericin B (AMB), and echinocandins (ECH) (caspofungin, anidu-
lafungin, and micafungin) are presented in Fig. 1. Most notably, C. auris is frequently
associated with high levels of FLU resistance, with multiple studies reporting resistance
in over 90% of isolates (4, 8–13). The heatmap clearly illustrates this point, where high
rates of resistance (red/orange) are pronounced across the globe, though notably low
rates of FLU resistance (11%) have also been reported in Colombia and South Korea
(14). AMB resistance, although not as pronounced as FLU resistance, is also a significant
issue because AMB resistance is extremely rare in other fungi, as it is thought to come
at a fitness cost to the organism (15). Resistance rates typically range up to 30% (4, 14),
with a small study from Venezuela having 50% resistant isolates (12). Several studies
have demonstrated elevated MICs for this polyene, ranging from 2 to 4 ␮g/ml, though
these are not as high as observed for other members of the Metschnikowiaceae family

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(16 ␮g/ml), which includes Candida haemulonii, Candida duobushaemulonii, and Can-
dida pseudohaemulonii (16). Interestingly, resistance to AMB within a Colombian isolate
cohort was shown to be geographically related, with resistance significantly associated
with hospital outbreaks in the northern region of the country compared to the central
region (14). It should be noted that the platform used to test AMB can have a bearing
on sensitivity, as it has been reported that the Vitek AST-YS07 card can provide
misleading and elevated AMB MICs (11). Therefore, standard CLSI broth microdilution
testing may be more a more accurate and reliable measure. Echinocandin resistance
remains limited, but unfortunately, it has been reported alongside other antifungal
resistance phenotypes. In one of the largest multicenter (10 hospitals) studies to date,
the resistance rates of 350 isolates collected from between 2009 and 2017 in India were
reported (8). Here, 2% of the isolates were resistant to echinocandins (⬎8 ␮g/ml),
alongside 8% resistant to AMB (⬎2 ␮g/ml) and 90% resistant to FLU (32 to ⱖ64 ␮g/ml).
Although termed as fungicidal agents against the majority of Candida spp., a recent
study of Columbian isolates revealed that both anidulafungin and caspofungin are in
fact fungistatic against C. auris in vitro (17). Assessment of echinocandin sensitivity
should be exercised with caution due to the paradoxical effect observed with caspo-
fungin; instead, micafungin or anidulafungin should be used for testing (18). The factors
driving echinocandin resistance are hospitals where these antifungals are recom-
mended as a first-line treatment or where other antifungals have failed. Irrespective, the
emerging landscape for C. auris antifungal resistance is the development of multire-
sistance phenotypes, driven by prior antifungal exposure and sequential antifungal
treatment failures (19–21). However, despite this pessimistic viewpoint, there appears
to be clade-specific sensitivity/resistance profiles; in India, for example, there are
significant levels of fluconazole sensitivity, whereas, other geographical sites have high
levels of multiazole resistance (6). In order to mitigate the development of multidrug
resistance, several in vitro studies have investigated the possibility of antifungal com-
binations. Indeed, the combination of micafungin with voriconazole was shown to
exhibit synergistic effects (22), as has also been reported for sulfamethoxazole-azole
combinations (23). These prove the possibility that C. auris infections can be managed
effectively, though in order to fully develop effective antifungal strategies, we must
understand what enables C. auris to withstand and respond to our antifungal arsenal.

OUR CURRENT UNDERSTANDING OF ANTIFUNGAL DRUG MECHANISMS

Antifungal resistance is generally driven by several factors, including point muta-
tions of the cellular target, overexpression of target molecules, and efflux pump
extrusion of antifungals (24). Mechanistically, the factors underpinning C. auris resis-
tance have become more apparent as we invested more resources to develop our
understanding, learning what we can from Candida albicans. Figure 2 illustrates some
of our current understanding of C. auris resistance mechanisms. Indeed, the first
multi-omics study comparing a clinically resistant (to FLU and ECH) isolate and a
sensitive C. auris isolate, alongside C. albicans, revealed drug resistance profiles distinct
from one another, with major differences in efflux pumps, cell wall, sterols, carbon
utilization, glycerolipids, and sphingolipids collectively playing a role in resistance,
albeit in a limited study of only two isolates (25). Moreover, the resistant isolate
displayed an enhanced biofilm proteome profile, a phenotype associated with adaptive
resistance. Comparing these isolates to Candida albicans ATCC 90028, it was shown that
both C. auris isolates had major differences with this regarding their carbon utilization
and downstream lipid and protein contents. Taken together, these data indicate that C.
auris displays a species-specific resistance profile.
Azole resistance is commonly mediated by amino acid substitutions in the lanosterol
14-alpha-demethylase (ERG11) gene, comprise multiple variant substitutions, including
Y132F, K143R, and F126L, and appear to be clade related (4). Heterologous expression
of C. auris ERG11-Y132 and ERG11-K143R alleles in Saccharomyces cerevisiae exhibited
increased MICs to both FLU and voriconazole. In contrast, heterologous expression of
two substitutions (I466M and Y501H) identified in isolates from the South American

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FIG 2 Conventional and phenotype-derived resistance mechanisms of Candida auris. Shown are various genetic
and phenotypic resistance mechanisms employed by C. auris. Circles indicate resistance to azoles (red), polyenes
(blue), and echinocandins (green). Figure was created with BioRender.

clade showed no effect on azole susceptibility (26). In addition, it has also been shown
that exposure to FLU can increase the expression of ERG11 up to 7-fold (8), and that an
increased copy number of ERG11 may also contribute to resistance (27). Indeed, a
subsequent investigation demonstrated that transient gene duplication of ERG11 and
CDR1 has the capacity to increase tolerance to FLU in older cells (28), an in vitro-
inducible upregulation of ERG11 validated elsewhere (8). Expanding our mechanistic
insights, recent work by Cowen’s group has implicated a role of the molecular chap-
erone Hsp90 for tolerance to azoles, whereas the efflux pump gene CDR1 played a
distinct role in high-level azole resistance that was revealed from deletion studies that
abrogated resistance (29). Corroborating these studies, efflux pump-mediated resis-
tance through an ATP-binding cassette (ABC) and the major facilitator superfamily
(MFS) has been shown to be significantly greater in a panel of C. auris isolates than in
Candida glabrata and C. haemulonii isolates (16). A recent study from Rybak et al. aimed
to functionally characterize the role for efflux pumps in triazole resistance in C. auris
(30). They demonstrated that the transcript levels of the CDR1 and MDR1 genes were
increased in triazole-resistant isolates in comparison to a fluconazole-susceptible iso-
late. Using a Cas9-ribonucleoprotein (Cas9-RNP) transformation system, they were able
to show that a Δcdr1 mutation in a resistant isolate was able to increase susceptibility
to fluconazole and itraconazole by 64- and 128-fold, respectively, with notable reduc-
tions in MIC also demonstrated in other azoles. The function of efflux pumps in azole
resistance appears to be predominantly associated with CDR1, as analysis of the Δmdr1
mutant showed minimal effect on increasing azole sensitivity (30), which is in line with
the aforementioned molecular analyses (29). Functional assays performed in biofilms
also support these findings (31).
Unlike azoles, the mechanism(s) governing resistance to polyenes are poorly un-
derstood in Candida species in general. Depletion of ergosterol composition through
loss-of-function mutations is thought to be the primary resistance mechanism in a
limited number of species, with erg3 mutations thought to be important in cross-
resistance (24). Whole-genome sequencing of resistant isolates identified four novel
nonsynonymous mutations, highlighting a potential association with resistance. These
mutations included those in genes with homology to the transcription factor Flo8 gene
of C. albicans and a membrane transporter (14). To understand the mechanisms
responsible for amphotericin B resistance, Muñoz and colleagues performed compar-
ative transcriptional analysis on a resistant isolate and a sensitive isolate after exposure

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to these drugs (27). Using RNA sequencing (RNA-seq), it was shown that 106 genes
were induced in response to AMB in the resistant isolate (27). Notably, genes involved
in the sterol biosynthetic process were identified, of which genes involved in the
ergosterol biosynthesis pathway were highly induced (ERG1, ERG2, ERG6, and ERG13),
which logically correlates with the maintenance of cell membrane stability. A limitation
of this entire approach is the comparative genomic nature, which may limit our future
discovery and understanding of novel antifungal-resistant genes specific to amphoter-
icin B and other agents.
Echinocandins are considered the first-line therapy for invasive infections, though
multiple studies have reported the isolation of resistant isolates across various geo-
graphical regions, with the highest levels of resistance reported in India (8, 32).
Resistance is typically associated with hot spot mutations in the FKS1 gene, which
encodes the 1-3-␤-glucan synthase enzyme, the target of echinocandins, resulting in
lower affinity of the enzyme to the drug (8). A study by Kordalewska and coworkers
identified that an S639F mutation in FKS1 conferred pan-echinocandin resistance in
four Indian isolates (18), with another study identifying a different amino acid substi-
tution in the same position (S639P) (33). Here, the interpretation of the paradoxical
effect becomes pertinent, as the high in vitro concentrations were not shown to
correlate in vivo with isolates not harboring the FKS1 mutation (18).

PHENOTYPE-DERIVED ANTIFUNGAL TOLERANCE

To combat both host and environmental stressors and selectively adapt to the
surrounding microenvironment, pathogenic fungi often employ unique phenotypes
that confer an advantage to colonize the surrounding environment. Phenotypic plas-
ticity has been extensively described in C. albicans, with the ability of the organism to
morphologically transform between yeast and hyphae and also switch between white
and opaque cell types the best understood mechanisms (34, 35). Phenotypic behavior
in C. auris is less well understood; however, various phenotypes have recently been
described that have been shown to have implications for antifungal resistance. A recent
study by Bhattacharya and colleagues demonstrated that transient gene duplication as
a result of replicative aging confers increased antifungal resistance in C. auris (28), as
has previously been described in C. glabrata and Cryptococcus neoformans (36, 37). The
authors showed that older C. auris cells of 10 generations displayed increased tolerance
across the four main classes of antifungals compared to that of a younger cell
equivalent (0 to 3 generations). Using FLU-susceptible isolates, it was shown that with
older generations of these isolates, cells could survive FLU concentrations of 256 ␮g/ml,
as well as be unresponsive to treatment in vivo using Galleria mellonella. This decreased
susceptibility was shown to be responsible for both increased expression and gene
duplication of CDR1 and ERG11. Another phenotypic difference which has been shown
in C. auris is through cellular aggregation. This phenomenon was first identified in
clinical isolates from the United Kingdom (38). It was shown that a subset of isolates
displayed an aggregative phenotype that could not be physically or chemically dis-
rupted with detergent. Interestingly, these aggregates were shown to be significantly
less virulent in a Galleria mellonella model, with single-celled isolates exhibiting viru-
lence comparable to that of C. albicans. A recent study from the same authors has now
identified that the ability to aggregate is indeed an inducible trait that can be
stimulated with prior exposure to triazole and echinocandin antifungals (39). These
findings were based upon the initial observation that isolates from the South African
clade naturally form aggregates and exhibit escalated MICs to triazoles. Exposure of
isolates to even low concentrations of triazoles and anidulafungin induced aggregate
formation in single-celled isolates of the South Asian clade but could not be induced
by polyenes or flucytosine. The mechanism by which cells aggregate to survive is
unknown, but the authors speculate that it could be linked to a stress response to
perturb ergosterol synthesis. The clinical implications of aggregation with regards to
antifungal resistance and environmental survival remain limited, but large aggregates
of cells have been recovered from harvested tissue of a murine model, suggesting that

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it may be used as a strategy to withstand host defenses (16). A recent study comparing
phenotypes of isolates from either colonizations or systemic infections identified the
ability to aggregate with a statistically significant association with colonization, sug-
gesting a role of this phenotype in persistence (40). More recently, we reported that
aggregating phenotypes enhance environmental survival through enhanced adhesion
and biofilm formation and recalcitrance to sodium hypochlorite treatment (41).
Biofilm formation is a well-studied mechanism by which many microbial pathogens
can confer increased resistance and tolerance to antimicrobials. Numerous pathogenic
fungi possess the ability to exist as these communities, with C. albicans and Aspergillus
fumigatus being the most extensively studied (42, 43). The ability of C. auris to form
biofilms was initially dismissed, although the semiquantitative methods used to draw
these conclusions were rudimentary (44). Clinically, C. auris has been recovered from a
variety of indwelling medical devices, including catheters, line tips, and neurological
shunts (16, 38, 45), as well as multiple fomites in the nosocomial environment and
reusable temperature probes (13), suggesting a role for biofilm lifestyle in both the host
and the environment. Indeed, more recent, in-depth analyses from a number of
different groups have demonstrated the potential of this pathogen to form antifungal-
tolerant biofilms (31, 46–50). A study by Sherry and colleagues first identified that C.
auris was able to produce intermediate quantities of biomass compared to C. albicans
and C. glabrata. Despite not producing biofilms as robust as those of C. albicans, these
communities were shown to tolerate the three major classes of antifungals, including
amphotericin B and micafungin, the recommended therapy for C. albicans biofilm
infections. Expanding on these findings, our group performed transcriptional analysis
to determine the underlying mechanisms associated with biofilm development and
tolerance (31). We demonstrated that tolerance to all classes of antifungals was
biofilm-phase dependent, with mature biofilms (24 h) exhibiting resistance to all three
classes of antifungals. Correlating with this was the increased expression of a number
of genes encoding efflux pumps of both ABC and major facilitator superfamily (MFS)
transporters. Inhibition of these transporters was shown to improve the susceptibility of
biofilms to fluconazole by 4- to 16-fold. Also upregulated during biofilm formation were
multiple glucan-modifying genes, which have key roles in biofilm extracellular matrix
formation. The matrix of C. auris has been shown to be both biochemically and
functionally similar to those of other Candida spp. in that is primarily composed of
glucan and mannan polysaccharides that can sequester azole antifungals (46). These
two mechanisms are conserved across biofilms formed by other Candida species and
likely explain the increased tolerance to azoles. Whether these observed mechanisms
also contribute to polyene and echinocandin tolerance associated with C. auris biofilms
individually or in combination remains unknown. However, given that these antifungals
are active against C. albicans biofilms, it is plausible to speculate that other novel
mechanisms may be involved, and as such, further work is required.

IMPLICATIONS FOR INFECTION CONTROL

Given the well-documented resistance profile of this pathogenic yeast and its
capacity to cause hospital outbreaks and high associated mortality rates, infection
control within the nosocomial environment is crucial. Multiple reports have suggested
that despite the implementation of more stringent infection control measures, that
cases of C. auris colonization and associated infections can continue (13). Unlike the
majority of other major Candida species which typically inhabit the gut and oral cavity,
C. auris readily colonizes the skin, which can be problematic for acquired nosocomial
infections. In addition, viable cells have also been recovered from various surfaces
within the environment, including bedding and flooring, as well as reusable equipment,
such as axillary temperature probes (13, 51). In vitro survival studies have shown that
the organism can survive for up to 28 days on different abiotic substrates, including
plastic and steel (52, 53).
Various studies have assessed the efficacy of routinely used commercially available
biocides against C. auris and have demonstrated optimal efficacy against the organism,

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with few exceptions (54–57). Quaternary ammonium-based agents have been shown to
have minimal efficacy against C. auris (55) and were used to clean reusable equipment
associated with an outbreak in Oxford (13). In addition, chlorhexidine has also shown
varied formulation-dependent efficacy, with resuspension of the active in 70% isopro-
pyl alcohol yielding more significant killing at a short contact time (56). It is worth
noting that the majority of disinfection studies have focused on testing in suspension,
which does not take into consideration the complex topographies of substrates and
surface-induced phenotypes employed by this organism. Adherent C. auris cells to
various hospital fomites have been shown to demonstrate reduced efficacy against
clinically relevant concentrations of sodium hypochlorite and peracetic acid (58). The
mechanisms employed to survive and persist in the environment are relatively un-
known, but there is mounting evidence to suggest that biofilm formation may be a
contributing factor, as has been suggested for MRSA (59). Ledwoch and Maillard
recently demonstrated using a dry biofilm model that C. auris could withstand and be
recovered following treatment with various biocides, in addition to showing significant
transferability to sterile surfaces (49). These findings are in agreement with those of our
recent study highlighting the expression of biofilm-associated characteristics after
14 days of survival (41). It was also shown that the aggregative phenotype may have a
function in environmental survival. Following treatment with sodium hypochlorite,
significant quantities of aggregative cells were recovered 2 weeks posttreatment,
compared to complete eradication of a single-celled isolate following treatment (41). In
addition, mature C. auris biofilms grown using a three-dimensional biofilm model can
tolerate both chlorhexidine and hydrogen peroxide treatment but remained suscepti-
ble to povidone iodine (60). Interestingly, the cell wall integrity pathway gene HOG1 has
been shown to regulate stress resistance, with C. auris displaying increased tolerance to
hydrogen peroxide compared to C. albicans (61). These molecular approaches are
therefore critical in the rationale design of new antifungals.

CANDIDA AURIS AND THE ANTIFUNGAL PIPELINE

With the alarming emergence of antifungal resistance, there is an increasing and
urgent need for the development of new antifungal therapies (62). The efficacy of the
existing arsenal has plateaued in recent years and is plagued with off-target effects and
bioavailability issues, coupled with the ever-increasing rise in antifungal-resistant iso-
lates (63). There are, however, a number of improvements to existing antifungals and
compounds with novel mechanisms of action which remain within the antifungal
pipeline and have shown promising activity against C. auris. These molecules include
expansions of current drug class targets, such as ␤-glucan synthase inhibitors, as well
as novel mechanisms of action targeting glycosylphosphatidylinositol (GPI) protein and
chitin synthesis. Ibrexafungerp (formerly known as SCY-078) is perhaps the most
promising and is currently in a phase 3 clinical trial for invasive candidiasis caused by
C. auris. It has been shown to have potent activity against C. auris in vitro, including
against echinocandin-resistant isolates (64). Furthermore, it possesses documented
antibiofilm activity, reducing both metabolic activity and biofilm biomass (48). The
novel, long-lasting echinocandin rezafungin (CD101) has also been shown to be active
against C. auris both in vitro and in vivo using a neutropenic mouse model (33, 65). It
does appear, however, to have reduced susceptibility to resistant isolates containing
the S639P FKS1 hot spot mutation (33). Another potential novel candidate is MYC-053,
which represents a new class of antifungals. It functions through a dual mechanism of
action in which it simultaneously inhibits both intracellular nucleic acid and targets
chitin synthesis of the cell wall (66). Data on its efficacy against C. auris are limited to
a single study; however, it has shown efficacy against azole- and echinocandin-resistant
isolates (66). Another antifungal molecule with a novel mechanism of action is APX001,
which blocks GPI protein synthesis via inhibition of the cell wall transfer protein GWT1.
It has been shown to have antifungal activity against resistant C. auris isolates (67), in
addition to having greater in vivo efficacy in an invasive candidiasis murine model than
anidulafungin (65).

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An attractive approach to combating antimicrobial resistance is the repurposing of

off-patent drug libraries. This “teaching an old dog new tricks” approach has been
employed across a number of pathogens of bacterial, viral, parasitic, and fungal origins
(68). Several libraries of compounds are readily available, which allows for the high-
throughput, nonbiased screening of compounds to identify potential novel activities,
with a number of studies already identifying molecules with antifungal activity
against C. auris. Screening of 1,280 small molecules from the Prestwick Chemical
library by Wall et al. identified the organoselenium compound ebselen to possess
significant antifungal activity against C. auris (69). Ebselen was shown to be active
against multidrug-resistant C. auris strains in both planktonic and biofilm forms, as
well as a large number of other clinically relevant yeasts and molds. Another
compound of interest identified from a repurposing library is alexidine dihydro-
chloride (70). Like ebselen, this molecule has broad-spectrum and antibiofilm
activity against a number of pathogens, including C. auris. Interestingly, this study
identified only 6 compounds from the repurposing library with activity against C.
auris, compared to 27 that were active against C. albicans, further highlighting the
resistant nature of this emerging pathogen (70). Another library screening study by
de Oliveira et al. identified a number of off-patent molecules with activity against C.
auris, including the aforementioned ebselen (71). Both this molecule and the antiplate-
let drug suloctidil exerted synergistic activity against a panel of C. auris isolates when
used in combination with voriconazole (71). Taken together, these molecules appear
promising for the future control of C. auris.

CONCLUDING REMARKS
The study of C. auris is in its relative infancy, though it has caused a sensation within
the medical mycology community and beyond due to its multidrug resistance “super-
yeast” persona. To our advantage, we have an army of skilled and willing researchers
with sophisticated multi-omic techniques that will enable us to tease out the most
salient and subtle of features, ultimately identifying the Achilles heel of this tolerant
yeast. It will also allow us to add to our understanding of how Candida spp. dynamically
adapt to a wide range of environments and stressors. Existing antifungal therapies are
limited and must be used cautiously when tackling culture-positive infections. There-
fore, augmenting antifungal therapies with novel agents in the antifungal pipeline is
our most promising of strategies, which will come to fruition over the next decade.

SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at https://doi.org/10.1128/
mSphere.00458-19.
TABLE S1, DOCX file, 0.1 MB.

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