fimmu-13-921483

REVIEW
published: 02 June 2022

doi: 10.3389/fimmu.2022.921483
Antimicrobial Resistance
in the COVID-19 Landscape:
Is There an Opportunity for
Anti-Infective Antibodies
and Antimicrobial Peptides?
José M. Pérez de la Lastra 1*†, Uttpal Anand 2*†, Sergio González-Acosta 1,
Manuel R. López 1, Abhijit Dey 3, Elza Bontempi 4 and Antonio Morales delaNuez 1
1Biotechnology of Macromolecules, Instituto de Productos Naturales y Agrobiologıá, IPNA (CSIC), San Cristóbal de la
Edited by:
Laguna, Spain, 2 CytoGene Research & Development LLP, Barabanki, Uttar Pradesh, India, 3 Department of Life Sciences,
Joveeta Joseph,
Presidency University, Kolkata, India, 4 National Interuniversity Consortium of Materials Science and Technology (INSTM) and
L V Prasad Eye Institute, India
Chemistry for Technologies Laboratory, Department of Mechanical and Industrial Engineering, University of Brescia, Brescia, Italy
Reviewed by:
Guangshun Wang,
University of Nebraska Medical Center,
United States Although COVID-19 has captured most of the public health attention, antimicrobial
Tejabhiram Yadavalli, resistance (AMR) has not disappeared. To prevent the escape of resistant
University of Illinois at Chicago,
United States microorganisms in animals or environmental reservoirs a “one health approach” is
*Correspondence: desirable. In this context of COVID-19, AMR has probably been affected by the
José M. Pérez de la Lastra inappropriate or over-use of antibiotics. The increased use of antimicrobials and
jm.perezdelalastra@csic.es
Uttpal Anand
biocides for disinfection may have enhanced the prevalence of AMR. Antibiotics have
ushuats@gmail.com been used empirically in patients with COVID-19 to avoid or prevent bacterial coinfection
†
These authors have contributed or superinfections. On the other hand, the measures to prevent the transmission of
equally to this work and share COVID-19 could have reduced the risk of the emergence of multidrug-resistant
first authorship
microorganisms. Since we do not currently have a sterilizing vaccine against SARS-
Specialty section: CoV-2, the virus may still multiply in the organism and new mutations may occur. As a
This article was submitted to consequence, there is a risk of the appearance of new variants. Nature-derived anti-
Microbial Immunology,
a section of the journal
infective agents, such as antibodies and antimicrobial peptides (AMPs), are very promising
Frontiers in Immunology in the fight against infectious diseases, because they are less likely to develop resistance,
Received: 15 April 2022 even though further investigation is still required.
Accepted: 06 May 2022
Published: 02 June 2022 Keywords: SARS-CoV-2, antibiotic resistance, one health approach, global health, antibiotic discovery,
antimicrobial peptides, environmental contamination, vaccination
Citation:
Pérez de la Lastra JM, Anand U,
González-Acosta S, López MR, Dey A,
Bontempi E and Morales delaNuez A
(2022) Antimicrobial Resistance
INTRODUCTION
in the COVID-19 Landscape:
Is There an Opportunity for
The COVID-19 pandemic has highlighted the susceptibility of humans to emerging infectious
Anti-Infective Antibodies and diseases (1). A serious threat to the world’s population is still faced by viral pandemics because many
Antimicrobial Peptides? viral diseases have no treatment and because of the emergence or re-emergence of some virus
Front. Immunol. 13:921483. strains. Scientists believe that the SARS-CoV-2 virus was first discovered in animals and then spread
doi: 10.3389/fimmu.2022.921483
Frontiers in Immunology | www.frontiersin.org 1 June 2022 | Volume 13 | Article 921483

Pérez de la Lastra et al. Antimicrobial Resistance in COVID-19 Landscape
to humans by crossing the species barrier. Like all other viruses resistance depend on the incidence and diversity of infections, as
belonging to the coronavirus family, SARS-CoV-2 can cause well as the availability, efficacy, and safety of the therapeutic
infection in both humans and animals, which means that approaches adopted (13, 14). Significant efforts are underway to
COVID-19 is a zoonotic disease or zoonosis (2, 3). Almost discover new classes of antibiotics and to develop derivatives and
75% of the emerging pathogens are zoonotic. The emergence drug combinations (15). The World Health Organization
of these new resistant microorganisms and their transfer between (WHO) warns that by 2050 there will be more deaths from
humans, animals, and ecosystems can be facilitated or impeded multidrug-resistant bacteria worldwide than from cancer (16).
because of environmental circumstances and behaviors (4–6). In Most countries have revealed that the process and development
today’s increasingly globalized society, an infected person is able of their AMR National Action plan has been affected by the
to spread the disease much faster than hundreds of years earlier. COVID-19 pandemic (Figure 1).
This finding has again highlighted the importance of the one Our goal is to analyze the factors associated with COVID-19
health approach to integrating human health, animal health, and which limit or promote the emergence of AMR. Knowledge of
the environment (7). the factors affecting this relationship will help mitigate the
Antimicrobial resistance (AMR) occurs when impact of the COVID-19 pandemic on AMR. In this scenario,
microorganisms (bacteria, fungi, viruses, and parasites) we encourage the investment in research and development of
undergo heritable changes when exposed to antimicrobial Nature-derived anti-infective agents; such as antimicrobial
agents such as antibiotics, antifungals, or antivirals. The peptides (17) and antibodies (18), which are distinguished by
development of resistant strains with a high potential for their limited ability to generate resistances (19).
infection occurs as a result of mutation or re-assortment of
pre-existing microbial strains, rendering vaccines and medicines
ineffective in some cases (8). The selective pressure exerted by IMPACT OF COVID-19 ON ANTIBIOTIC
antimicrobials induces mechanisms for the acquisition of PRESCRIPTION
resistance in microorganisms, such as spot mutation or
horizontal gene transfer, which pass from generation to At social level, COVID-19 has enabled greater visibility of
generation and therefore select microorganisms that have infectious diseases (1, 20). One potential consequence of the
inherited this resistance (9, 10). Although several classes of COVID-19 pandemic is the spread of antimicrobial resistance in
broad-spectrum antibiotics are available to treat Gram-positive the acute care setting because of the increased antimicrobial use
and Gram-negative bacterial infections, many pathogens rapidly (21). In hospitals, antibiotics have been used intensively in
evolve or acquire resistance to first-line treatments and respond patients with COVID-19 to eliminate potential bacterial
only to last-resort antibiotics (11, 12). An infection caused by infections (22, 23). Up to 70% of patients with COVID-19
resistant microorganisms is more difficult to treat. Affected receive antibiotic treatment, either on an outpatient or
people may require hospitalization, generate more clinical inpatient basis. Antibiotics cannot destroy viruses. However,
complications, and, eventually, may result in the patient physicians often need to prescribe antibiotics to hospitalized
becoming a carrier of the AMR with the possibility of patients with COVID-19 who have a confirmed or strong
transmitting the infection to those around him/her. In most suspicion of bacterial coinfection or superinfection (24).
cases, the severity of disease associated with the emergence of Sometimes physicians do not have sufficiently knowledge of
FIGURE 1 | World map showing the countries (in blue) that, during 2020-2021 responded favorably to the question “Has your National AMR Action Plan
development and implementation process been affected by the COVID-19 pandemic and the national response in your country?”. Countries in red are those who
responded negatively. Source: Global database for the Tripartite Antimicrobial Resistance (AMR) Country Self-Assessment Survey (TrACSS) https://
amrcountryprogress.org.

the symptoms and natural course of respiratory infectious The destruction of forests and the expansion of urban areas and
diseases and prescribe empiric antibiotics, even if the diagnosis industrial activity can be dangerous for a wide range of animal
is not microbiologically confirmed. One of the main reasons of species. The survivors are forced to be closer to each other and
antibiotics prescription is due the symptoms of COVID-19, that humans, which makes it more likely that harmless animal microbes
often resemble to those of bacterial pneumonia (25). Diagnostics will turn into deadly human pathogens. The COVID-19 pandemic
used to distinguish viral from bacterial pneumonia may be is supposed to have begun in bats and spread from a “wet market”
ineffective or have response times of hours or days, while in Wuhan, China, where live wildlife species are available for
immediate treatment is needed. In addition, bacterial infections human consumption. Selling wild animals for human use, whether
in patients who do not have COVID-19 can go unnoticed and as pets or in the form of live animal markets, plainly poses a
require delayed treatment when all focus is on pandemic control. significant danger to public health. These marketplaces serve as
Patients with COVID-19 may also be affected by a secondary breeding grounds for zoonotic infections by housing ill, stressed,
bacterial infection requiring antibiotic treatment, contributing to and overcrowded animals in extremely unclean settings. The
an increased use of these drugs (26–28) (Figure 2). There is a risk continued use of these procedures will cause further disasters to
that a large number of people may use antibiotics in an erroneous human health in the future, with the potential for much
self-medication attempt to protect themselves from the virus. greater devastation.
This might be particularly common in underdeveloped countries A key factor in the development of bacterial resistance is the
where antibiotics can be available without a prescription. ability of the microorganism to adapt rapidly to new
Currently, the impact of the pandemic on the prevalence of environmental conditions (32). In industrial livestock models,
multidrug-resistant (MDR) bacteria is still unclear. More and the widespread and indiscriminate use of antibiotics and growth
better data are needed to better understand the incidence of co- promoters exacerbates the problem by producing pathogenic
infections and the pathogens involved, as well as the impact of strains resistant to these drugs. Despite bans in different
underlying risk factors on patients. Recent reports have countries, antibiotics are being used in animal husbandry, not
described a high use of broad-spectrum antibiotics as a risk only to treat infections but also to promote weight gain in
factor in the emergence of multidrug-resistant microorganisms, animals such as cattle, pigs, and poultry (33). The overuse of
which often appear in critically ill COVID-19 patients (29–31). antimicrobial drugs in farm animals and human medicine has
been linked to the emergence of multidrug-resistant microbes
(34, 35). About 65 percent of all antibiotics used for human
treatment (including tetracyclines and penicillins) are marketed
IMPACT OF COVID-19 ON THE RELEASE for animal use in the United States. Most of them are
OF ANTIMICROBIALS INTO administered to entire groups of animals, even if none of them
THE ENVIRONMENT are sick. As a result, antimicrobial drugs become ineffective and
infections persist in the organism, increasing the risk of spread to
Habitat degradation is an important factor in the increasing threat other people or animals (36). Humans can become infected with
posed by pandemics and other human health problems. antibiotic-resistant bacteria through handling or eating raw or
FIGURE 2 | Impact of COVID-19 on antibiotic prescribing. One of the potential consequences of the COVID-19 pandemic is the spread of antimicrobial resistance in
the acute care setting as a result of increased antimicrobial use. Although antibiotics cannot destroy viruses, physicians are sometimes insufficiently aware of the
symptoms and natural course of respiratory infectious diseases and often prescribe antibiotics to those diagnosed patients in whom there is confirmation or high
suspicion of bacterial coinfection or superinfection. Consequently, many hospitalized patients with COVID-19 are prescribed empirical antibiotics, often in the
absence of microbiological confirmation of the diagnosis.

undercooked meat, coming into contact with livestock or their native biota. Environmental remediation and biogeochemical
excrement, and/or eating food or drinking water (including cycling of elements might be disrupted by the introduction of
recreational water) contaminated with animal feces. Antibiotics these chemicals into soil. The presence of these biocides can
are one of the most frequently found chemicals in aquatic interfere with wastewater treatment methods that rely on the
environments worldwide. This might have serious activity of microorganisms that play key roles in biogeochemical
consequences for the ecology as well as the spread of AMR in cycles and environmental remediation (42–44). Although
the environment. Alternative livestock production techniques ethanol is the predominant ingredient in most hand hygiene
are promoted by agroecology by reducing pesticide use and products, some gels also incorporate other synthetic substances
increasing soil fertility in ecological ways. that may not offer much in terms of protection but instead may
The pandemic led to some livestock animals being kept on fuel bacterial antimicrobial resistance (45). This may result in the
farms longer than usual because of problems with transportation selective survival of bacteria harboring resistance genes, and in
and outbreaks at the slaughterhouse. This may have contributed the development of AMR (46–48). During the COVID-19 crisis,
to increasing animal density on farms, which may have resulted the massive use of these substances, in particular in hospitals,
in greater antibiotic administration in animal production. and the continued use of these hand hygiene products can lead to
Preventive use of antibiotics in farmed animals was recently unintended release of biocides and disinfectants into
prohibited by the European Union. It is expected that other wastewater and sewage treatment plants (49, 50). As a result of
nations follow suit for genuine success in the battle against AMR. extraordinarily high bacterial loads combined with
Hand washing is considered an essential means of preventing subtherapeutic drugs, wastewater is a significant source of
nosocomial infections, mostly in healthcare settings. Hand AMR, causing the selective survival of bacterial strains carrying
hygiene is highly recommended to prevent the acquisition and resistance genes (6, 39) (Figure 3).
transmission of SARS-CoV-2 infection (37). The advent of
COVID-19 has led to an increase in the consumption of
antibacterial soaps, hydroalcoholic gels, and other IMPACT OF COVID-19 VACCINATION ON
handwashing products and disinfectants (38, 39). It has THE EMERGENCE OF RESISTANCE
become so popular that, at least in developed countries, almost
all stores, schools, hospitals, and workplaces carry these hand The use of vaccines may minimize resistance to the pathogens
hygiene products to prevent the acquisition and transmission of targeted by vaccination. Vaccines are an important tool in the
infections (38, 40). Hand hygiene products typically contain prevention of infections and have had a positive impact on the
bactericidal, fungicidal, and virucidal products, as well as reduced use of antibiotics and the development of antibiotic
alcohol and non-alcohol detergents, but some manufacturers resistance (51). Vaccination prevents infectious diseases and
add antimicrobial compounds to make the product more their complications; is easy, cheap, and saves lives (52).
effective against pathogens (41). These chemicals, like Conventional vaccines may lower viral loads, thereby
hydrogen peroxide and sodium hypochlorite, peroxyacetic acid, decreasing onward transmission. Vaccine protection is twofold:
and chlorine dioxide may penetrate soil systems and damage it protects the inoculated person to prevent infection, and on the
FIGURE 3 | Impact of COVID-19 on the release of antimicrobials into the environment. The excessive use of antimicrobial drugs in farm animals and human
medicine, especially in hospitals, can lead to an increase in the concentration of biocides and disinfectants in wastewater and sewage treatment plants and cause
the selective survival of bacterial strains carrying resistance genes.

other hand, it can protect the surrounding people, even those variability (72, 73). For example, the effort to avoid a double
who are not immune to the disease, since the immunized person health burden of “flu and COVID-19” has led to increased flu
is unable to spread the infection, a concept named “herd vaccination coverage and this may have influenced less
immunity” (53). When a vaccine stops people from getting the antibiotic prescribing for flu-like infections and secondary
virus or bacteria, it gives them sterilizing immunity. This means bacterial complications.
that they can’t have enough viruses in their bodies to spread to
other people. In contrast, vaccines that cause “non-sterile”
immunity protect the host from the disease but do not stop
the disease from spreading. prevent the emergence of new IMPACT OF OTHER MEASURES
variants and reduce the development of resistance, it is FOR THE PREVENTION OF
essential that the virus cannot replicate among infected people, COVID-19 TRANSMISSION
so vaccines that provide sterilizing immunity or measures that
prevent the colonization of the virus in tissues are desirable (54, With the COVID-19 pandemic, measures such as lockdowns,
55). The administration of COVID-19 vaccination, and other physical distancing, travel restrictions, and quarantines
vaccines for simultaneous co-infections, are anticipated as a safe implemented for persons in close contact with a positive have
and effective measure to prevent infections (56) and further been implemented. These measures may have contributed to a
evolution of variants (57). The new COVID-19 vaccinations have reduction in the opportunities for transmission of many
the potential to reduce the usage of antibiotics for COVID-19 pathogens beyond SARS-CoV-2 (74). On the other hand,
patients (58). However, current COVID-19 vaccines do not transmission within a local household or facility may be
prevent vaccinated people from infecting themselves and amplifying (75). Generally, the situation of confinement, and
others. As a result, anybody who contracts the virus, regardless the limitation in leaving home, could have contributed to a
of vaccination status, has the potential to spread it, which makes decrease in the number of medical visits and, therefore, to a
herd immunity an unrealistic goal (59). Given that the scientific decrease in antibiotic prescriptions (76) limiting the appearance
community currently accepts that both vaccinated and of resistance microorganisms (Figure 4).
unvaccinated people can be a source of infection for others, the In general, the use of facemasks is a key strategy for the
sanitary utility of the green pass for the prevention of COVID-19 effective prevention of airborne diseases. The use of facemasks
infection is questionable (60, 61). Without additional control potentially blocks airborne transmission routes and it is
measures to discriminate against infection, this action could recognized as an effective containment measure in the
enable to an increase in the burden of disease among those COVID-19 pandemic: indeed, it prevents droplet dispersal
vaccinated in these local contexts required by the passport. when infected persons talk, sing, cough, or sneeze (77). Then,
The rapid development of COVID-19 vaccines and the fear of facemasks can reduce the risk of environmental contamination
side-effects has raised doubts about the safety and efficacy of by respiratory droplets and the spread of the virus among people.
vaccination among certain groups of people (62). If the benefits/ In addition, the possible virus diffusion by contact can be
risks of vaccination are not correctly explained to the population, avoided, due to the limitation of respiratory droplets that may
this perception could negatively affect the acceptance of “normal” deposit onto surfaces. Facemasks also provide a physical
vaccines, such as measles and polio. Focusing excessive attention obstruction that prevents the wearer from touching his or her
on the pandemic could also have led to substantial disruption of face, thereby reducing fomite transmission (78). In the pandemic
other global health programs, including routine childhood scenario, mask use helps minimize the spread of SARS-CoV-2
vaccination campaigns against cholera, measles, meningitis, infection by the wearer (79, 80). It is not surprising that health
polio, tetanus, typhoid, and yellow fever. This situation could authorities recommend the use of facemasks to reduce the risk of
increase the number of people with no defense against these environmental contamination and disease transmission. Finally,
diseases and their associated complications, and the occurrence this reduces the need to use antimicrobials, and the risk of
of resistance (63, 64). emerging resistant microorganisms (80).
As long as the virus continues to be spread, there is the With the pandemic, administrations and health authorities
possibility that new variants may appear that are more have promoted telemedicine, where physicians can prescribe
contagious, produce more severe symptoms, or evade the effect medications. It is possible that this would force doctors to
of vaccines (65, 66). The rapid global spread of the delta variant prescribe drugs without being able to auscultate, or take a
was explained by the maintained viral load despite increasing sample, to establish a true diagnosis. In this scenario, it can be
vaccination coverage (67, 68). Current vaccines only target the postulated that, on occasion, doctors may have over-prescribed
spike protein (S), that provides the cellular entry of the virus antibiotics, as a conservative attitude (81–83). Although limiting
through the ACE2 receptor (69, 70). However, this protein can social contacts, this measure could negatively impact the
accumulate a higher rate of mutations among other SARS-CoV-2 appearance of resistant microorganisms (Figure 4). The
proteins, and thus may contribute to escape immunity (66, 71). extended use of hand hygiene products containing biocides is
To improve the protection against mutant strains and reduce the another measure that could result in the release of chemicals into
use of antibiotic, future COVID-19 vaccines should target other the environment facilitating the emergence of resistant
antigenic viral proteins with the capacity to induce less epitope microorganisms (Figure 4).

FIGURE 4 | Measures that prevent the spread of SARS-CoV-2 infection may have an impact on the emergence of resistant microorganisms. Vaccination, the use of
facial masks, and measures limiting social contacts may result in a decrease in antibiotic prescriptions, limiting the appearance of resistant microorganisms. However,
the use of biocide-containing hand hygiene products, telemedicine, and self-prescribing may have increased the use of antibiotics and the release of biocides into
the environment, facilitating the emergence of resistant microorganisms.
THE NEED FOR NEW ANTIMICROBIALS commercialization of a new antibiotic (91, 92). This, coupled
with the fact that bacteria can develop resistance mechanisms
Most of the currently available antibiotics were discovered that make them unusable, makes them unattractive to the
between 1940 and 1960 (84, 85). However, by the mid-1960s the pharmaceutical industry. Furthermore, this low profitability
rate of identification of new and efficient structures had declined would be influenced by the possibility of marketing generic
dramatically (86). Until the 1980s, the lack of new discoveries of antibiotics ten years after their introduction on the market
antimicrobials was compensated by the pharmacological study (93, 94).
and optimization of existing antibiotics. Particularly the study of Due to the current difficulties in obtaining new classes of
the biochemical mechanisms that describe both the action of drugs antibiotics, we are now approaching a situation of inability to
on their targets, and their associated resistance was largely control infections (95). If new drugs are not developed, deaths
investigated. This era was defined by the obtaining of a large due to antibiotic resistance are expected to exceed 10 million per
number of optimized derivatives through the synthesis and year by 2050 (96). The problem is that infectious diseases are
chemical modification of existing antibiotics with improved estimated to become the leading cause of death, ahead of cancer
activities and broader spectra (87). In the 1990s, a new wave of and cardiovascular diseases (89).
resistance has resulted in significant in projects to identify new In the current COVID-19 pandemic, the focus of the
classes of molecules in the antibiotic capacity (86). This discovery pharmaceutical industry has been to develop vaccines and
was based on the rational design of molecules, genomic analysis effective antimicrobials against SARS-CoV-2 (97). However, we
platforms, and combinatorial chemistry, coupled with should not forget the need for new antimicrobials, as the
computational tools. However, the race to generate new emergence of AMR is likely to increase, impacting COVID-19
antibiotics by pharmaceutical companies was later abandoned. morbidity and mortality. Therefore, any antimicrobial strategy to
The main reason was the null permeability of the new compounds find new structures of more efficient anti-infectives should be
obtained, which prevented them from crossing the bacterial wall to promoted. Compounds with a broad spectrum of action and less
exert their antibiotic activities (88). During evolution, the resistance are particularly desirable.
molecular tools necessary to develop a resistance mechanism
have always been accompanied by the natural ability of
microorganisms to generate antibiotics. Thus, we could predict ANTIMICROBIAL PEPTIDES AND
that eventually, new resistance mechanisms will emerge in ANTIBODIES AS ANTI-INFECTIVE DRUGS
response to the use of the latest generation of antibiotics (89). A
major concern for microbiologists and infectious disease Anti-infective treatment is based on the principle of targeting
authorities is the continuous increase in resistance and the rapid molecular pathways that cause infection but do not impair
spread among strains of a microorganism and the lack of effective bacterial growth. In the face of a shortage of new antibiotics,
antibiotics (90). antimicrobial peptides and specific antibodies, are gaining
The development and manufacture of new antimicrobials is a attention as Nature-derived anti-infective agents with great
long process. It can take more than 10 years from discovery to clinical potential (98, 99). Antimicrobial peptides (AMPs) and

antibodies both play an important role in the defense against events and contribute to infection removal (99). The flexibility
foreign microorganisms and are part of innate and acquired to generate antibodies against any target, the ability to alter
immunity, respectively. They both have less capacity to generate effector functions, half-life, and the size of treatment units, are
resistance in target microorganisms and can be administered particularly well suited for customizing therapies to specific
together with other antibiotics or antimicrobial compounds. infectious agents (103). Proteins on microbe surfaces, toxins,
AMPs are a rapid, non-specific means of combating a wide and other virulence factors can all be targets for antibodies.
variety of bacteria, fungi, viruses, and even protozoa (100). Enzyme areas crucial for microbial metabolism can also be
Specific antibodies are essential macromolecules for the targeted by antibody design, being able to influence the activity
adaptive immune systems of all vertebrates. Defense blood cells of antigen molecules without necessarily affecting the immune
are also important producers of AMPs, where they constitute response (105).
part of the non-oxidative effector mechanisms against potential Antibody-based treatments, such as pathogen-specific
pathogens (101). AMPs are synthesized mainly in epithelial monoclonal antibodies (MAbs), have demonstrated promise in
tissues regularly exposed to microbial attacks such as skin, the treatment of bacteria (e.g., MRSA) and viruses that are
intestine, and lungs. In the body, AMPs are synthesized up to resistant to conventional antibiotics (106). Over 40 antibody-
a hundred times faster than antibodies and at much lower based drugs have been authorized or are pending approval. The
metabolic cost, can be stored in high concentrations, are selectivity of the antibodies translates into the very minimal off-
available for immediate action, and are released or produced target binding and hence very few side effects, including the
when cells are stimulated by contact with microorganisms (102). gastrointestinal problems sometimes associated with antibiotics
However, antibodies only recognize a single infectious agent, and due to their wide impact on the gut bacterial flora in the
even while mutations of that agent may render the antibody environment (99). However, certain characteristics of
useless, this does not affect other similar agents and does not monoclonal antibodies make them less suited when compared
contribute to the spread of resistance (103). Faced with a market to other antimicrobial therapies (103). The first is the high
where cheap and effective antibiotics are accessible, the production cost. Because of the widespread use of broad-
manufacture of AMPS and antibodies for biomedical spectrum antibiotics, antibody-based treatments are less
applications exhibit inherent constraints; such as high interesting to the pharmaceutical industry. Antibodies are
production cost, storage conditions, and dosage for proteins, they must be handled with care, kept cold, and be
administration (104) (Table 1). injected intravenously or subcutaneously (103). Antibiotics, on
In the context of COVID-19, excessive antibiotic prescribing, the other hand, are generally formulated as pills or tablets that
the increased use of biocides, and the agricultural use of may be used orally and stored at room temperature. Antibiotics
antibiotics can contribute to the emergence of resistant target general mechanisms in bacteria, such as cell wall
microorganisms. Conventional antibiotics generally target formation, and can be effective against a wide range of
metabolic enzymes that may selectively develop resistance, bacteria. Antibodies, on the other hand, are very specific to a
whereas AMPs and antibodies kill microbes or neutralize single virus, bacterium, or bacterial subtype. Antibody therapy
infectious pathogens, thus making it inherently more difficult provides an immediate level of immunity, and a clear diagnosis
for the organisms to develop resistance. They can be regarded as must be made before starting treatment with a monoclonal
safe and effective templates for the generation of future antibody. For example, antibody treatment has been
antimicrobials (104) (Figure 5). administered to patients with recurrent C. difficile infections
(107). However, several advancements, including dosage, cost,
Antibodies and Antibody-Derived Therapies and biologic stability, remain for the normal use of MAb
Antibodies and antibody-derived therapies provide an intriguing administration for AMR prevention (103). A larger and more
set of tools and properties for killing or neutralizing infectious realistic context should be used to evaluate the trade-off between
pathogens, lysing infected cells, or modulating the immune antibody treatments and antibiotics in terms of cost and
system to allow effector cells to escape immunosuppressive convenience of use in the clinic (103). This includes the
TABLE 1 | Different features of antibiotics, antibodies, and antimicrobial peptides as anti-infective agents for infectious diseases.
Feature Antibiotics AMP Antibodies
Cost of production Low High High/moderate

Storage conditions Room temperature Refrigerated Refrigerated
Administration Orally (tablets) Topical/systemically iv/sc injection
Target specificity Narrow Broad/narrow Narrow
Resistance Yes Difficult No
Structure Simple, homogeneous,well-characterized Diverse, homogeneous, well-characterized Complex, heterogeneous, and less characterized
Molecular weight Low (<1kDa) <5 kDa High (>50 kDa)
Degree of instability Low High Low
Risk of immunogenicity Low Low High
Mechanisms of action Generally specific Variable or still unknown Specific

FIGURE 5 | In the current COVID-19 scenario, antibody-based treatments such as pathogen-specific monoclonal antibodies (MAbs) and antimicrobial peptides
(AMPs) could limit the development of resistant microorganisms as they are considered to generate little or no resistance.
current COVID-19 scenario surrounding the development of interact electrostatically with the negatively charged
resistance to antimicrobial drugs (97). A few MAb-based drugs environment of bacterial membranes and to stabilize the
are currently authorized for use by the US FDA in infectious binding. On the other hand, hydrophobicity makes these
disorders (Table 2). New antibody-based therapies to treat and peptides more permeable to the lipid bilayer and they can bind
prevent bacterial-associated pneumonia are being developed to each other and form pores in bacterial membranes (102). The
(112). Chicken polyclonal antibodies against SARS-CoV-2 have formation of pores in the bacterial membrane leads to its
been proposed as anti-infective treatments for COVID-19 (113). destabilization and allows the entry and exit of metabolites,
Antibody-based drugs will continue to play an essential role in inducing bacterial lysis. Many antimicrobial peptides act on the
the development of new infectious disease treatments in the bacterial membrane that has evolved. To generate resistance to
future (99). It is envisaged that some of these initiatives will show AMPs, bacteria must restructure the architecture of their cell
clinical success and hence provide the foundation and membranes, a process that will take several generations and
enthusiasm for this process (114). multiple mutations. This fact means that AMPS are considered
to generate little or no resistance (102, 119).
Antimicrobial Peptides Structurally, antimicrobial peptides are widely categorized
AMPs usually exhibit broad-spectrum antimicrobial activity, into four large classes based on the polypeptide chain bonding
although some AMPs may exhibit bacteriostatic, types: class O (circular), class P (resembling a P-shape, where a
immunomodulatory, anti-inflammatory, and antitumor activity chemical bond is formed between the sidechain of one amino
(115, 116). All these properties make AMP substances with great acid and the backbone of another amino acid in the chain), class
pharmacological potential (117, 118). One advantage of AMPs is S (containing a chemical bond between different sidechains), and
their action on biological targets, other than traditional class L (linear peptides). This classification is also named UCBB,
antibiotics, and their multiple mechanisms of action (117). UCSB, UCSS, and UCLL, respectively (120). Some antimicrobial
Although AMPs are very diverse structurally; many show some peptides have a simple helix or sheet structure, whereas others
common features, such as their positive net charge and their high are more complex. According to how cells can synthesize AMPs,
hydrophobicity. These two properties allow them to interact with they can be classified as ribosomal or non-ribosomal. Non-
lipid membranes (119). The net positive charge is essential to ribosomal peptides are generally synthesized by bacteria and
TABLE 2 | MAbs approved by the US FDA for treatment of infectious diseases.
mAb Target Format Indication Ref
Palivizumab RSV Humanized IgG1 Prevention of respiratory syncytial virus infection (108)
Raxibacumab B. anthrasis PA Human IgG1 Anthrax infection (109)
Bezlotoxumab C. difficile enterotoxin B Human IgG1 Prevention of Clostridium difficile infection recurrence (107)
Obiltoxaximab B. anthrasis PA Chimeric IgG1 Prevention of inhalational anthrax (110)
Ibalizumab CD4 Humanized IgG4 HIV infection (111)

assembled by cytosolic multi-modular enzymes, whereas barriers, potential immunogenicity, and the difficulty of
ribosomal peptides are gene-encoded and usually result from conferring oral bioavailability to these molecules (114). Many
the cleavage of a pre-propeptide (102). antimicrobial peptides are nephrotoxic due to their high
The large diversity of cationic peptides has been hypothesized therapeutic dosage and several AMPs have failed in Phase III
to derive from their antibacterial role in combating the distinct clinical trials due to lack of clear efficacy or lack of superiority
pathogenic microorganism issues faced by each host organism over conventional treatments (117).
(119). Nature contains an almost unlimited number of peptide
drugs that need to be pharmacologically characterized (121, 122).
Templates for the development of new antimicrobial agents can CONCLUSIONS
be found from creatures that live in germ-filled habitats, which
can penetrate bacterial membranes (123, 124). The Public actions to mitigate COVID-19 have resulted in a change in
Antimicrobial Peptide Database APD (https://aps.unmc.edu/ the public’s behavior regarding the adoption of preventive
home) collects the characteristics and activities of more than measures. Some measures, such as face masks, social distancing,
3000 antimicrobial peptides from six life kingdoms. Animal- and increased hand hygiene will likely diminish AMR. In contrast,
derived AMPs such as magainins, dermaseptins, and other over-prescription of antibiotics, nosocomial infections, and
AMPs isolated from frog skin, are being studied as potential telemedicine could have contributed to an increase in AMR
therapies for skin infections as both therapeutic and preventative (131–133). Everything seems to indicate that this new virus,
agents in humans. Because topical antimicrobial peptide SARS-CoV-2, is contributing to worsening the current situation
treatment prevents systemic toxicity, many antimicrobial concerning the emergence of resistant microorganisms (19, 21).
peptides have been developed as topical applications (102). AMR demands a “one health” approach, which recognizes that
Despite the growing interest in AMPs as broad-spectrum, non- human and animal health are interrelated, and that infections are
resistance-generating antibiotics, only a few AMPs have been transmitted from people to animals and vice versa. These changes
approved by the US FDA for clinical use (117, 125) (Table 3). in the everyday use of antibiotics and other substances could result
Nisin has been approved for the treatment of stomach ulcer in the release of antibiotics and resistant bacteria into the
and colon infections. Currently, nisin is the only non-ribosomal ecosystem via contaminated water, food, or excretion.
antimicrobial peptide commonly utilized in food preservation Consequently, the spread of AMR across many domains of one
being an additive for the agricultural and food industries. health, such as healthcare, agriculture, and the environment, might
Daptomycin is a 13 amino acid cyclic lipopeptide generated by be affected. A global vision of the pandemic impact on AMR is not
the bacteria Streptomyces roseosporus. It has bactericidal known yet and can only be speculated at this point. However, it is
effect against Gram-positive bacteria, including those that reasonable to suppose that new treatments and vaccines designed
are resistant to antibiotics. The combination of peptide to restrict the spread of SARS-CoV-2 should limit the
antibacterial capabilities with antibiotics has the potential to development of resistant microorganisms and vice versa. The
reduce the development of resistance. For example, when the decline in the investment and lack of innovation of antibiotics
antimicrobial peptide. AMPs may interact synergistically with also favors the emergence of antimicrobial-resistant organisms
immune system components in addition to having synergistic (89, 133). Current vaccines against COVID-19 have not been
activity when coupled with antibiotics and could be potential implemented globally. There are still countries where there is a
alternatives to conventional antibiotics due to their favorable very little vaccination (97, 134). The lack of sterilizing vaccines to
safety profile and low or limited ability to induce bacterial prevent human-to-human transmission might increase the risk of
resistance (102). Cathelicidins are one of the most promising the emergence of new variants of SARS-CoV-2 and enhance the
antimicrobial peptides. However, there are intrinsic adverse impact of COVID-19 on AMR (62). In the context of anti-
characteristics of antimicrobial peptides that still make them infective therapy, Nature derived anti-infectives have the potential
unattractive to the pharmaceutical industry: such as their to be helpful as a part of the arsenal to combat AMR infections
stability, adsorption, inability to cross epithelial and skin (114). They are particularly useful as can be co-delivered with
TABLE 3 | Natural AMPs approved by the US FDA for clinical use.
AMP Source Mechanism Target Indication Ref
Nisin Lactococcus lactis Inhibit cell wall synthesis Broad spectrum activity Treatment of stomach ulcer and colon
infections (126)
Melitin Apis mellifera Membrane disruption Broad spectrum activity Relieving pain and swelling
(127)
Gramicidin Brevibacillus brevis Membrane disruption Gram-positive bacteria Ophthalmic purposes
(128)
Daptomycin Streptomyces Inhibits cell wall synthesis Gram-positive bacteria Skin infections
roseosporus (129)
Polymyxins Paenibacillus polymyxa Insertion of the AMPs into the MDR Gram-negative Eye and wound infections
membrane bacteria (130)

existing antibiotics. More research and development are still valuable suggestions. ANN: Writing-review & editing,
required to view the true potential of these agents as powerful response, valuable suggestions. All authors have read and
tools against drug-resistant pathogens. However, new antibody- approved the final version of the manuscript for submission to
based drugs or AMPs might establish their relevance and make a this journal.
difference in some infectious disease sectors. If these expectations
are satisfied, a new generation of antimicrobial medications that
are flexible, powerful, and long-lasting will be accessible soon.
FUNDING
AUTHOR CONTRIBUTIONS This research was funded by projects “Agencia Canaria de
Investigació n, Innovació n y Sociedad de la Informació n
All the authors of this manuscript have substantially contributed (ACIISI) del Gobierno de Canarias” (project ProID2020010134),
to the concept, literature mining, writing and methodology of the and CajaCanarias (project 2019SP43). MRL acknowledges
review, provided critical feedback and revised the manuscript contract (IMMUNOWINE) financed by Cabildo de Tenerife,
critically. All authors contributed to the writing or revision of the Program TF INNOVA 2016-22 (with MEDI & FDCAN Funds).
final manuscript. JMPL: Conceptualization, literature survey, AMN is a recipient of a postdoctoral Marie Curie fellowship under
writing-original draft preparation, prepared the tables and grant agreement 101030604 (IGYMERA). The funders had no
figures, data validation, revised the manuscript, formal role in the design of the study; in the collection, analyses, or
analysis, supervised the drafting process of the review, project interpretation of data; in the writing of the manuscript, or in the
administration and funding acquisition. UA: Conceptualization/ decision to publish the results.
conceived the study idea, planned and designed the review
structure, wrote the first draft of the manuscript, visualization,
response, suggestions, revision, final draft. SG-A: Writing—
review & editing, prepared tables and figures, completed the ACKNOWLEDGMENTS
critical revision of the entire manuscript. MRL: Writing-review &
editing, completed the critical revision of the manuscript, All the authors are highly grateful and acknowledge the authority
response, suggestions, and arranged references. AD, and EB: of the respective departments and institutions for their support
Writing-review & editing, overall proofreading, response, in carrying out this research.
10. Bell G, MacLean C. The Search for ‘Evolution-Proof’antibiotics. Trends

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Feature Antibiotics AMP Antibodies

Cost of production Low High High/moderate

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TABLE 2 | MAbs approved by the US FDA for treatment of infectious diseases.

mAb Target Format Indication Ref

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TABLE 3 | Natural AMPs approved by the US FDA for clinical use.

AMP Source Mechanism Target Indication Ref

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10. Bell G, MacLean C. The Search for ‘Evolution-Proof’antibiotics. Trends

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