Mwangi (2019)

ZOOLOGICAL RESEARCH
Antimicrobial peptides: new hope in the war against

multidrug resistance
James Mwangi1,2,3, Xue Hao1, Ren Lai1,3,4,5,6, Zhi-Ye Zhang1,*
1
Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese
Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming Yunnan 650223, China
2
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming Yunnan 650204, China
3
Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming Yunnan 650223, China
4
Institutes for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai 201203, China
5
KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese
Academy of Sciences, Kunming Yunnan 650223, China
6
Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan Hubei 430071, China
ABSTRACT killing action, broad-spectrum activity, and

extraordinary clinical efficacy against several MDR
The discovery of antibiotics marked a golden age in strains. Therefore, this review highlights multidrug
the revolution of human medicine. However, resistance among nosocomial bacterial pathogens
decades later, bacterial infections remain a global and its implications and reiterates the importance of
healthcare threat, and a return to the pre-antibiotic AMPs as next-generation antibiotics for combating
era seems inevitable if stringent measures are not MDR superbugs.
adopted to curb the rapid emergence and spread of
multidrug resistance and the indiscriminate use of Keywords: Multidrug resistance; Nosocomial
antibiotics. In hospital settings, multidrug resistant infections; Antimicrobial peptide; Antibiotic
(MDR) pathogens, including carbapenem-resistant alternatives
Pseudomonas aeruginosa, vancomycin-resistant
enterococci (VRE), methicillin-resistant INTRODUCTION
Staphylococcus aureus (MRSA), and extended-
spectrum β-lactamases (ESBL) bearing A perturbing prediction by the World Health Organization
Acinetobacter baumannii, Escherichia coli, and (WHO) is that by the year 2050, drug-resistant infections,
largely exacerbated by the indiscriminate use of antibiotics,
Klebsiella pneumoniae are amongst the most
will kill 10 million people annually, ignite a financial cataclysm,
problematic due to the paucity of treatment options,
and impose extreme poverty upon millions of people (de
increased hospital stay, and exorbitant medical
Kraker et al., 2016). The increasing incidence and prevalence
costs. Antimicrobial peptides (AMPs) provide an
of antibiotic resistance among nosocomial bacterial pathogens
excellent potential strategy for combating these
and the rapid spread of resistance genes in the environment
threats. Compared to empirical antibiotics, they
show low tendency to select for resistance, rapid
Received: 23 July 2019; Accepted: 26 September 2019; Online: 26
Open Access September 2019
This is an open-access article distributed under the terms of the Foundation items: This work was supported by the National Natural
Creative Commons Attribution Non-Commercial License (http:// Science Foundation of China (21761142002 and 31801975), Chinese
creativecommons. org/licenses/by-nc/4.0/), which permits unrestricted Academy of Sciences (XDB31000000, SAJC201606, KFZD-SW-219-
non-commercial use, distribution, and reproduction in any medium, 2, KFJ-BRP-008, and KGFZD-135-17-011), and Yunnan Province
provided the original work is properly cited. Grant (2015HA023)
Copyright ©2019 Editorial Office of Zoological Research, Kunming *
Corresponding author, E-mail: zhangzhiye@mail.kiz.ac.cn
Institute of Zoology, Chinese Academy of Sciences DOI: 10.24272/j.issn.2095-8137.2019.062
488 Science Press Zoological Research 40(6): 488-505, 2019

are major global healthcare threats due to the associated associated with growing death tolls and huge economic
increase in morbidity and mortality and huge burden on the burdens due to increased disability and high medical costs
economy (Aslam et al., 2018; Zaman et al., 2017). (Jing et al., 2019; Peters et al., 2019). Currently, common
Since the discovery of penicillin in 1928 by Alexander problematic MDR bacteria include methicillin-resistant S.
Fleming, antibiotics have saved countless lives and marked aureus (MRSA), vancomycin-resistant MRSA, MDR P.
an important medical revolution in plant, animal, and human aeruginosa, carbapenem-resistant A. baumannii, E. coli, and
prophylaxis. Unfortunately, the continued use of antibiotics K. pneumoniae, vancomycin-resistant enterococci (VRE), and
has been accompanied by the rapid emergence and spread of extensively drug-resistant (XDR) Mycobacterium tuberculosis
multidrug resistant (MDR) strains and many medical (Levin et al., 1999; Miller et al., 2005). Recent reports have
specialists are warning of an inevitable return to the pre- also indicated cases of bacterial strains completely resistant
antibiotic era (Adedeji, 2016). For example, bacterial genomic to all available antibiotics. For example, the extensive use of
analysis has revealed the presence of more than 20 000 colistin, a drug of last resort for the treatment of MDR
genes associated with resistance (Liu & Pop, 2009), with a pathogens such as P. aeruginosa, A. baumannii, and K.
higher number expected over the coming years. Therefore, pneumoniae in both human medicine and agriculture, has led
stringent measures are necessary to curb the spread of to the emergence of a plasmid-mediated MCR-1 gene that
resistant strains as they present a major challenge to global encodes for its resistance (Liu et al., 2016; MacNair et al.,
public health not only in the war against microbial infections, 2018; Paterson & Harris, 2016).
but also in other clinical applications such as cancer The increasing incidence of infections resulting from MDR
treatment, invasive surgery, and graft transplantation (Gudiol pathogens in clinical settings has intensified the demand for
& Carratalà, 2014; Lupei et al., 2010). alternative therapies. Antimicrobial peptides (AMPs) with
Several factors that have been implicated in the current potent antimicrobial activities and diverse mechanisms of
upsurge of antimicrobial resistance (AMR) in hospitals and the action (MOA) are considered important alternatives to solving
community, including the indiscriminate use of antibiotics in the issues of multidrug resistance.
human and animal medicine and in agricultural practices
involving growth promoters (Silveira et al., 2009; van Boeckel
IMPLICATIONS OF MULTIDRUG RESISTANCE IN
et al., 2015), lack of proper regulation regarding over-the-
counter antibiotics, especially in developing countries where NOSOCOMIAL PATHOGENS
they are easily available without proper medical prescription
(Ayukekbong et al., 2017), and poor sanitation practices Epidemiological surveillance data worldwide indicate that
leading to the introduction of unmetabolized antibiotics into anomalous use of antibiotics has resulted in the evolution of
the environment through human and animal waste (Davies & several human pathogens into MDR strains that are highly
Davies, 2010). tolerant or resistant to antibiotic therapies, thus posing a
Natural selection is an inherent process and key driver of serious threat to public health (Davies & Davies, 2010; WHO,
evolution, conferring organisms with traits for increased 2014). Multidrug resistance, especially in nosocomial
environmental adaptability and survival (Jesus et al., 2002). pathogens, is of great clinical concern due to the increased
Over the years, the widespread use of antibiotics has led to morbidity and mortality and enhanced virulence and
the selection of diverse strains of microorganisms possessing transmissibility (Bhat et al., 2006; Khan et al., 2017). Such
MDR traits or genes (Martínez & Baquero, 2002; Ochoa et al., pathogens are implicated in severe infections such as
2009). Such resistance-conferring properties, through ventilator-associated pneumonia (Koenig & Truwit, 2006) as
bacterial and genomic associations, can be easily transferred well as bloodstream (Martinez & Wolk, 2016), surgical site
across different ecological niches, e. g., from animals to (Anderson, 2011), and implant-associated urinary tract
humans and vice versa, and from hospital settings to the infections (Nicolle, 2014). These infections occur often and
community, where they present an unprecedented crisis are severe in immunocompromised patients, although recent
(Groisman & Ochman, 1996; Kümmerer, 2004; Phillips et al., evidence also suggests the spread of MDR genes into the
2004). general community (Khan et al., 2017).
In bacteria, mechanisms conferring resistance to almost all For gram-negative nosocomial pathogens, especially A.
available classes of antibiotics have been studied extensively baumannii, P. aeruginosa, K. pneumoniae, S. aureus, and
and described in detail in previous literature (Blair et al., 2014; Enterobacter spp., the emergence of multidrug resistance to
Dever & Dermody, 1991; Lin et al., 2015; Lombardi et al., several available classes of antibiotics, such as penicillins,
2019; Morita et al., 2012). These mechanisms include aminoglycosides, cephalosporins, and fluoroquinolones, has
enzymatic degradation of antibiotics, drug-target modification, increased over the years as a result of extensive use,
altered membrane permeability, and enhanced expression of especially in intensive care units (Richard et al., 1994;
efflux pumps that actively eliminate antibiotics (Alanis, 2005; Struelens, 1998). In many cases, these MDR strains show
Laxminarayan & Brown, 2001; Munita & Arias, 2016). reduced susceptibility to all available antibiotic therapies and
Initially associated with severe nosocomial infections in are implicated in serious high mortality rate-nosocomial
immunocompromised patients, multidrug resistance has infections (Hirsch & Tam, 2010; Manchanda et al., 2010).
spread to the wider community, resulting in severe infections Colistin, an AMP consisting of two polypeptides (polymyxin A
Zoological Research 40(6): 488-505, 2019 489

and B), is often used as a drug of last resort for MDR strains, also resistant to most other antibiotics and the transfer of
notwithstanding its adverse side effects such as nephrotoxicity vancomycin-resistant genes can occur from enterococci
and neurotoxicity, due to the paucity of treatment options strains to even more lethal pathogens such as MRSA,
(Falagas et al., 2005; Yamamoto et al., 2018). However, therefore leaving very few or no therapeutic options (Chang et
current reports indicate the emergence of MDR strains that al., 2003; Franchi et al., 1999; Noble et al., 1992).
exhibit reduced susceptibility to colistin following long-term Bacterial biofilms are of great clinical significance to global
clinical or laboratory exposure (Jeannot et al., 2017). healthcare due to their important role in nosocomial and
Resistance to colistin is attributed to the presence of the MCR- implant-related infections. Most nosocomial pathogens
1 gene, which is highly transmissible across different bacterial produce biofilms, which complement disease pathogenicity
strains and has been isolated from strains on hospital and resistance (Dunne, 2002; Gurung et al., 2013). Biofilm-
surfaces and in animal and clinical human samples producing organisms such as A. baumannii and P. aeruginosa
(Yamamoto et al., 2018). These strains also exhibit low exhibit extreme resistance to almost all antibiotics compared
susceptibility to almost all other antibiotics, including those with non-biofilm-producing microorganisms. Biofilms form a
designated as "last-resort" such as polymyxins (colistin) and protective coating around bacterial cells, thus hindering the
carbapenems, thus raising a new crisis in the war against killing action of antibiotics (Stewart, 2002). Other factors that
multidrug resistance (Liu et al., 2016; Rapoport et al., 2016; contribute to resistance in biofilm-producing organisms
Yamamoto et al., 2018). include the formation of persister cells (dormant and highly
Gram-positive S. aureus is another important nosocomial resilient to almost all available antibiotics), slow bacterial
pathogen and is transmitted through direct contact with growth within the biofilm, and adaptability to stressful
contaminated surfaces, clinical waste, open wounds, and conditions (Keren et al., 2012; Lewis, 2008).
clinical staff (Denis, 2017; Price et al., 2017). It is a major Multidrug resistance to useful classes of antibiotics has
cause of skin infections, sepsis, and pneumonia in increased gradually among several bacterial nosocomial
hospitalized patients, with recent data indicating increased pathogens. Thus, great efforts have been expended on the
incidences of community-acquired S. aureus infections due to discovery of novel antibiotic alternative therapies. Currently,
improper disposal of hospital waste, poor hygiene, and the several AMPs with potent efficacy are under clinical trial and
spread of resistant genes to the community (Dotel et al., present excellent mitigation strategies for the multidrug
2017). The rising incidence of MRSA infections is a growing resistance crisis (de Breij et al., 2018; Koo & Seo, 2019;
healthcare threat associated with increased mortality rates in Stefania et al., 2015). Moreover, compared with traditional
hospitals and the community (Othman et al., 2019). antibiotics, AMPs possess many important qualities that make
Additionally, most MRSA strains exhibit resistance to all other them excellent candidates for therapeutic exploitation. For
antibiotics, including the beta-lactams, and recent reports instance, AMPs are multifunctional with diverse MOA,
indicate the emergence and spread of strains with reduced
including membrane disruption, inhibition of DNA and protein
susceptibility to glycopeptide compounds such as vancomycin
synthesis, and impairment of key cellular processes such as
(vancomycin-resistant MRSA), therefore making treatment
metabolism and cell wall synthesis (Kumar et al., 2018; Tzong-
almost impossible (Bhat et al., 2006; Centers for Disease &
Hsien et al., 2016; Wimley, 2010). Their diverse MOA are
Prevention, 1997; Othman et al., 2019).
important as they minimize the tendency of pathogens to
Over the past few years, enterococci, which are normal flora
select for resistance, as observed in most conventional
of the gut and genital tract, have become problematic
antibiotics that only act on single targets unless used in
nosocomial pathogens and a growing clinical predicament.
combination (Alanis, 2005; Bechinger & Gorr, 2017).
This trend is concomitant with their inherent resistance to
Moreover, most AMPs exhibit potent antimicrobial properties
several commonly used drugs, including penicillin, ampicillin,
against both gram-negative and gram-positive bacteria, fungi,
cephalosporin, and clindamycin (Gold & Moellering, 1996). In
and viruses in the nanomolar and micromolar range (Frecer et
addition to inherently acquired resistance, enterococci can
al., 2004; Wakabayashi et al., 1996; Yamauchi et al., 1993),
rapidly acquire resistance to virtually any antibiotic either
rapidly kill pathogens within minutes, and have a low proclivity
through rapid mutation or the acquisition of foreign genetic
to select for resistance compared with conventional antibiotics
material, thus expressing a repertory of resistance
(de Breij et al., 2018; Nagarajan et al., 2019).
mechanisms to antibiotics such as enhanced expression of
efflux pumps, modification of drug targets, and enzymatic
degradation of drug agents (Linden, 2002). MDR enterococci AMPs: ORIGIN AND PROSPECTS
exhibit high adaptability under antibiotic pressure and can
rapidly acquire resistant genes to enhance their survival. One AMPs or host defense peptides are a notably class of
notable example is the rapid transfer of resistant genes compounds of the innate immune system with both
associated with the extensive use of vancomycin among microbicidal and immunomodulatory activities, providing a first
several strains of enterococci, especially Enterococcus line of defense against pathogenic invasion (Falanga &
faecalis and Enterococcus faecium, two important nosocomial Galdiero, 2018; Kang et al., 2017; Pasupuleti et al., 2012).
pathogens (Arias & Murray, 2012). Resistance to vancomycin AMPs are polypeptides of varying molecular weight and
presents a major clinical crisis as most of these strains are amino acid residues (ranging from five to over 100) and are
490 www.zoores.ac.cn
found in virtually all living organisms, from simple prokaryotes Levin et al., 1999; MacNair et al., 2018).
to complex eukaryotes (Figure 1). They play important roles in In vertebrates, AMPs can directly kill microorganisms and
the direct killing of infectious agents, viruses, bacteria, fungi, play a role in immunomodulation through the activation and
and parasites and through the modulation of immune recruitment of immune cells during infection (Kumar et al.,
processes such as activation and recruitment of immune cells, 2018; Mahlapuu et al., 2016). Several different classes of
wound healing, angiogenesis, and inflammation (Haney & AMPs, such as cathelicidins and defensins, have been
Hancock, 2013; Kumar et al., 2018; Maróti et al., 2011; isolated and characterized from immune cells, bodily
Oppenheim et al., 2003; Zhao et al., 2013). secretions, and epithelial tissues of amphibians and marine
and terrestrial animals (Lu et al., 2008; Wang et al., 2016). For
example, several AMPs have been identified from amphibian
skins, where they are produced in glands of the dermal skin
layer and released following pathogenic exposure, inducing a
microbicidal action through membrane disruption (Rollins-
Smith et al., 2005; Woodhams et al., 2007). In humans,
psoriasin, dermcidin, and lactoferrin are continuously secreted
by the sweat glands to form an important barrier against
infection, and cathelicidin LL-37 is secreted following microbial
introduction (Harder et al., 2013). Nearly 30 cathelicidins have
Figure 1 Number of natural and synthetic antimicrobial peptides been characterized from domestic and wild mammals
from different kingdoms (total 3 011) as of July 2019 (Kościuczuk et al., 2012), and are stored as inactive
Data obtained from antimicrobial peptide database http://aps. unmc. precursors in neutrophil granules and activated following
edu/AP/ (Wang et al., 2016). microbial exposure (Treffers et al., 2005). Apart from
cathelicidins, several other classes of antimicrobial peptides
have been isolated and identified in vertebrates (Brogden et
In most organisms, high concentrations of AMPs are
al., 2003; Zhang, 2006; Zhang et al., 2008). These AMPs have
expressed on surfaces that are constantly exposed to
diverse MOA and play multifunctional roles, including
pathogens. For example, the mucosal lining and skin of
modulation of immune responses, prevention of excessive
vertebrates display broad-spectrum antimicrobial activities
tissue damage, alleviation of inflammation, and destruction of
(Brogden et al., 2003; Rinaldi., 2002). In general, AMPs are
invading pathogens to mitigate infection onset (Haney &
either produced continuously or up-regulated following
Hancock, 2013; Maróti et al., 2011; Oppenheim et al., 2003).
exposure to a threat (Ganz, 2003). For example, human skin
Several vertebrate AMPs show excellent therapeutic
is continuously protected by an abundance of psoriasin,
potential due to their antibacterial, antiviral, antifungal, and
dermcidin, and lactoferrin, with cathelicidin LL-37 also up- anti-inflammatory properties (Oppenheim et al., 2003; Qi et
regulated following infection (Harder et al., 2013). In bacteria, al., 2019), whereas others show improved clinical efficacy,
AMPs play an important role in enhancing adaptability and structural stability, and potent antimicrobial activity against
survival during antagonistic competition for resources with several MDR pathogens following modification (Kumar et al.,
other bacteria occupying the same ecological niche (Kumar et 2018; Schmidtchen et al., 2014; Zhang et al., 2019).
al., 2018). Several peptides with potential therapeutic activity In contrast to vertebrates, insects and plants lack an
have been isolated from bacteria and demonstrate potent adaptive immune system, relying entirely on the innate
antimicrobial activities against both gram-negative and gram- immune system for defensive purposes, with AMPs playing a
positive bacteria and even fungi. These AMPs are known as pivotal role in the protection against invading pathogens.
bacteriocins and play important roles in inhibiting or killing Several AMPs have been isolated and analyzed from the
antagonistic bacterial strains with no self-harm, thus epithelial cells, hemocytes, and hemolymphs of insects
conferring a critical survival strategy (Yang et al., 2014). (Brown et al., 2009; Hancock et al., 2006; Philippe & Reto,
Bacteriocins provide important prospects for the development 2005). Peptides isolated from insects are usually cationic and
of alternative antibiotic strategies against different bacterial kill bacteria through permeabilizing bacterial membranes, and
pathogens and are also useful in the food industry as further possess potent microbicidal activity either singly or
preservatives (Mills et al., 2011; Silva et al., 2018). Bacteria- synergistically with traditional antibiotics (Yi et al., 2014).
derived AMPs include nisin, a 34-amino acid residue peptide Notable examples of insect-based AMPs include cecropins,
and an important food preservative isolated from Lactococcus defensins, drosocins, and diptericins, which exhibit activities
lactis (Tong et al., 2014), and colistin, isolated from against both gram-negative and gram-positive bacteria as well
Paenibacillus polymyxa and used extensively in agriculture as fungi (Mylonakis et al., 2016; Rozgonyi et al., 2009; Wu et
and human prophylaxis (Poirel et al., 2017). Colistin is an al., 2018; Zhang & Gallo, 2016).
important last-resort peptide drug used against several MDR AMPs also play important defensive roles in plants (which
nosocomial pathogens such as MRSA, MDR P. aeruginosa, also lack an innate immune system). Several peptides have
and carbapenem-resistant pathogens, although its use is been isolated and characterized from the leaves, roots, seeds,
somewhat limited due to its side effects (Falagas et al., 2005; and tubers of plants (Tam et al., 2015). Generally, they exhibit

high proteolytic, thermal, and chemical stability due to the important members of this group and are found widely in
presence of multiple disulfide bonds conserved within their nature in all vertebrates (Kościuczuk et al., 2012). For
rich cysteine residues (Hammami et al., 2009; Hilchie et al., example, LL-37, a prominent cathelicidin in humans, exhibits
2013; Stotz et al., 2009; Tam et al., 2015). Plant AMPs have broad-spectrum microbicidal activities against gram-positive
been extensively studied and discussed (Craik, 2012; and gram-negative bacteria by plasma-membrane disruption
Hammami et al., 2009; Nawrot et al., 2014; Stec, 2006). Much (Björstad et al., 2009). LL-37 has been extensively studied
like AMPs from vertebrates, plant-based AMPs confer and used as a template for the design of several synthetic
protection against invading pathogens through membrane AMPs, many of which are currently under clinical trial (de Breij
disruption and pore formation and by targeting key microbial et al., 2018; Dürr et al., 2006; Kościuczuk et al., 2012). Other
processes such as DNA and protein synthesis (Nawrot et al., α-helical AMPs include aurein from the granular dorsal glands
2014). Notable examples of plant AMPs include plant of the frog Litoria aurea (Rai & Qian, 2017), melittin from
defensins and thionins (Hilchie et al., 2013; Stotz et al., 2009). honey-bee venom, and cecropin derived from the hemolymph
Plant defensins are small cationic peptides with 45–55 amino of Hyalophora cecropia (Yi et al., 2014).
acid residues and exhibit potent antibacterial and fungal The β-sheet peptides, which constitute the largest group of
activities (Gao et al., 2000; Tavares et al., 2008). Thionins are AMPs, are produced in many organisms such as marine
cationic peptides with 45–48 amino acid residues and three or invertebrates, amphibians, plants, and animals (Haney &
four disulfide bonds (Stec, 2006). They exhibit potent activities Hancock, 2013; Maróti et al., 2011; Oppenheim et al., 2003;
against bacteria and fungi and cytotoxicity on animal cells Wang et al., 2016) and show both antibacterial and antifungal
(Evans et al., 1989; Fernandez De Caleya et al., 1972). properties (Harwig et al., 1996). In contrast to α-helical
Used singly or in combination with traditional therapeutics, peptides, these peptides are ordered in aqueous solution and
AMPs are quite effective at combating infectious agents, contain conserved cysteine residues that form disulfide bonds
including MDR bacteria. They exhibit potent microbicidal that enhance structural stability and minimize proteolytic
activity in the micromolar range, rapid killing action, and low degradation (Tzong-Hsien et al., 2016). They exhibit
selection of resistance, thus constituting an important strategy boundless therapeutic prospects, e. g., as antifungal,
for curbing MDR pathogens (Deslouches & Di, 2017; Loeffler antibacterial, antiviral, and anti-inflammatory agents, and
et al., 2001; van't Hof et al., 2001). In contrast to empirical primarily kill bacteria through plasma-membrane disruption
antibiotics that target single or specific bacterial processes, (Kumar et al., 2018; Panteleev et al., 2015). Prominent
AMPs exhibit multifunctional bacterial killing effects, including members of this family include defensins, protegrins, and
disruption of the plasma membrane, and also target microbial tachyplesins. Defensins are found in plants, invertebrates, and
intracellular processes, including inhibition of transcription and vertebrates and exhibit activity against both gram-positive and
translation, protein synthesis, and bacterial cell wall formation gram-negative bacteria, fungi, and viruses (Panteleev et al.,
(Gee et al., 2013; Hurdle et al., 2011; Reddy et al., 2004). 2015; Yamaguchi & Ouchi, 2012). Tachyplesins, a class of
Presently, much effort is being directed toward obtaining peptides isolated from hemocytes of the horseshoe crab,
novel antimicrobial agents with broad-spectrum activity exhibit strong microbicidal activity, although their use is
against pathogenic microorganisms. Naturally occurring AMPs hampered by their potential toxicity to mammalian cells
have proven to be invaluable templates for the design and (Edwards et al., 2017; Liu et al., 2018; Miyata et al., 1989).
synthesis of synthetic AMPs with increased potency, which are The third class of AMPs include those with an extended-coil
easier to produce and less sensitive to proteolytic degradation structure. These AMPs lack secondary structures present in
(Falanga et al., 2016; Hurdle et al., 2011). other AMPs such as α helices and β sheets and mostly
consist of specific amino acid residues including arginine
CLASSIFICATION AND STRUCTURE OF AMPs (Arg), proline, or tryptophan (Mahlapuu et al., 2016). They
exhibit broad-spectrum activity against gram-negative bacteria
via membrane disruption and targeting internal processes and
With more than 3 000 sequences reported to date, AMPs are
also possess antitumor activity (Falla et al., 1996). Important
often classified based on their secondary structures and MOA.
extended-coil AMPs include indolicidin, a 13-amino acid
Based on structure, the three currently established classes
peptide produced by bovine leukocytes that shows potent
include α-helical, β-sheet, and extended-coiled peptides
antimicrobial activity (Falla et al., 1996), as well as tritrpticin
(Figure 2) (Falanga & Galdiero, 2018; Lombardi et al., 2019).
(Yang et al., 2002) and human salivary histatin (Du et al.,
The α-helical AMPs are unordered in aqueous solution but
2017).
once in contact with a biological membrane, they assume an
amphipathic α-helical structure (Kumar et al., 2018). Important
α-helical AMPs include magainin, a 23-amino acid residue MECHANISM OF ACTION (MOA) OF AMPs
peptide isolated from the skin of the African clawed frog
(Xenopus laevis), which exhibits highly potent tumoricidal and For AMPs, there is strong evidence suggesting a close
broad-spectrum antimicrobial activities against bacteria, fungi, correlation between their MOA and physical features or
and protozoa due to membrane disruption (Matsuzaki, 1999; primary structure, which are characterized by a net positive
Zerweck et al., 2017). The cathelicidin family of AMPs are also charge and hydrophobicity (Figure 2) (Dathe & Wieprecht,
Figure 2 Structural diversity and helical wheel projections of representative AMPs
A: α-helical-magainin (PDB ID 2LSA). B: β-sheet-chicken ovo-defensin (PDB ID 2MJK). C: Extended coil-tritrpticin. Images were created with
Protein Data Bank (PDP) (Bioinformaticsdoi:10.1093/bioinformatics/bty419) (Rose et al., 2018) and visualized with Jmol software. D: Helical
wheel projections of four representative peptides showing physical properties canonical to all AMPs, including distribution of amino acid residues,
net charge, and hydrophobicity established to correlate with antimicrobial activity, selectivity, and cytotoxicity. Positively charged residues (polar) are
represented as blue circles and hydrophobic (nonpolar) residues are yellow circles. Wheels projections, net charge, and hydrophobicity of AMPs
were generated with HeliQuest webserver (http://heliquest.ipmc. cnrs.fr/).
1999; Matsuzaki, 1999). The cationic charge influenced by Hydrophobicity is crucial for peptide selectivity to biological
amino acid residues such as Arg and lysine (Lys) enhances membranes and increased hydrophobicity is correlated with
selectivity for negatively charged bacterial plasma membranes increased hemolytic activity as highly hydrophobic AMPs
while exhibiting low electrostatic interactions with the have a stronger ability to penetrate the hydrophobic core of
uncharged outer layer of the eukaryotic cell membrane erythrocyte membranes (Chen et al., 2007; Tachi et al.,
(Guilhelmelli et al., 2013). Current efforts at improving the 2002).
selectivity for and electrostatic interaction of AMPs with Understanding the MOA of AMPs is paramount for
bacterial membranes involve the substitution of amino acids unlocking their full potential as next-generation antibiotics.
with positively charged amino acid residues like Arg and Lys Extensive research has been conducted, and is still ongoing,
(Arias et al., 2018; Yeaman & Yount, 2003). For example, Jin to unveil the MOA of AMPs (Guilhelmelli et al., 2013; Hancock
et al. (2016) reported that substitution of amino acids & Lehrer, 1998; Ulm et al., 2012). Based on their MOA, AMPs
improved antimicrobial efficacy, increased stability, and can be classified into those that kill through membrane
reduced the hemolytic activity of the designed peptide ZY13 disruptive mechanisms and non-membrane disruptive
compared to its precursor peptide cathelicidin-BF15. mechanisms, as illustrated in Figure 3. For the membrane
Previous studies have also indicated a strong correlation disruptive killing action, AMPs produce microbicidal activity by
between the cationic charge of an AMP and its antimicrobial targeting and disrupting the bacterial plasma-membrane
activity, with data showing improved antimicrobial activity of structure, mostly through permeabilization, thus resulting in
several AMPs against both bacterial and fungal pathogens leakage of intracellular content (Huang et al., 2010). An
paralleled with an increase in cationic charge (Gagnon et al., important aspect to consider for this MOA is the concentration
2017; Hong et al., 2001; Lyu et al., 2016); however, increased threshold of peptide molecules on the bacterial membrane
hemolytic activity has been observed for several AMPs surface for effective permeabilization via interaction of
following an increase in net charge (Chen et al., 2005; Jiang positively charged AMP residues with negatively charged
et al., 2008). Secondly, hydrophobicity is an important moieties on the bacterial membrane surface (Chen et al.,
parameter of all AMPs and is attributed to a substantial 2007; Shai, 2002). To drive this membrane disruptive MOA,
proportion (almost 50%) of hydrophobic residues in peptide three models have been postulated, i. e., barrel-stave, carpet-
sequences, such as leucine, valine, isoleucine, alanine, like, and toroidal pore models. For all models, the MOA begins
methionine, tyrosine, tryptophan, and phenylalanine. with the accumulation and organization of AMP molecules

parallel to the membrane surface, followed by electrostatic wide range of immune cells, including phagocytes,
interaction between the AMPs' cationic charged residues and neutrophils, and macrophages, and are involved in the
negatively charged phospholipids on the membrane surface mitigation of infection such as controlled secretion of
(Falanga et al., 2016). proinflammatory cytokines to prevent cytokine storm and
Typical for α-helical AMPs, the barrel-stave model tissue damage, recruitment and activation of immune cells,
constitutes the formation of hydrophilic pores on the promotion of angiogenesis, and suppression of excessive
hydrophobic core of the bacteria membrane structure, reactive oxygen species release (Hancock et al., 2012; Hilchie
resulting in membrane disruption and leakage of extracellular et al., 2013; Nicole et al., 2012; Nijnik & Hancock, 2009). For
content (Kumar et al., 2018). For the carpet-like mechanism, example, human cathelicidin LL-37 exhibits
peptide molecules accumulate parallel to the membrane immunomodulation properties such as chemoattraction and
surface in a carpet-like fashion, followed by penetration into activation of various immune cells such as monocytes,
the membrane and disruption of the lipid bilayer (Brogden, neutrophils, and mast cells by using formyl peptide receptor-
2005; Falanga et al., 2016; Rodríguez-Vázquez et al., 2014). like 1 (De et al., 2000; Nijnik & Hancock, 2009). A thorough
In contrast, toroidal pore models, e. g., magainin peptide, understanding of the antimicrobial and immunomodulatory
cause membrane disruption by perpendicular insertion into properties of AMPs provides excellent opportunities for the
the lipid bilayer (Shai, 2002; Wimley, 2010). discovery and design of novel therapies for bacterial infection
Direct killing through non-membrane disruptive mechanisms as well as inflammatory and cardiovascular diseases such as
involves targeting microbial processes or physiological atherosclerosis and thrombosis (Bei et al., 2019; Zhang et al.,
functions other than the cell membrane, utilizing similar killing 2015).
mechanisms as those by conventional antibiotics such as
inhibition of cell wall, protein, and DNA synthesis and reduced
enzymatic activity (Hancock & Rozek, 2002; Hancock & Sahl, ACTIVITY OF AMPs AGAINST MDR NOSOCOMIAL
2006). Firstly, the AMP interacts with the plasma membrane BACTERIAL PATHOGENS
before penetrating with or without membrane permeabilization
(e. g., activity of buforin II on E. coli) and accumulating The rapid spread of antibiotic resistance presents a daunting
intracellularly, where it targets and acts on key processes clinical challenge due to the recalcitrance of pathogens to
such as transcription and translation, protein synthesis, traditional antibiotics, especially among nosocomial
enzymatic activity, and microbial death (Brogden, 2005; Park pathogens. In both developing and developed countries,
et al., 1998). For example, human α-defensin 1, human α- hospital-acquired infections, commonly referred to as
defensin 5, human β-defensin 4, and indolicidin all have nosocomial infections, are a growing concern often associated
intracellular targets (Falla et al., 1996; Lehrer et al., 1989; with prolonged hospital stay, increased mortality rates, and
Sharma & Nagaraj, 2015). huge economic burden. Therefore, the discovery of novel
In addition to direct microbial killing, AMPs are required for alternative therapies is paramount. Several AMPs have been
other immunomodulatory functions. They are secreted by a found to show potent microbicidal activity in the micromolar
Figure 3 Schematic of membrane disruptive and non-membrane disruptive bacterial killing mechanisms of AMPs
Illustration created with BIORENDER.COM.
range against several bacteria strains, with a low likelihood for potential and reduced side effects (Chou et al., 2008; Liu et
selection of resistance, therefore creating hope in the war al., 2015). Such strategies have focused on improving
against MDR pathogens (Deslouches & Di, 2017; Loeffler et efficacy, structural stability, and protection from proteolytic
al., 2001; van't Hof et al., 2001). degradation, and include chemical modifications such as
Natural and synthetic peptides have proven to be effective acetylation, enrichment with non-natural D-amino acids,
in combating several pathogens, including MDR gram-positive substitution of amino acid residues, and use of delivery
and gram-negative bacteria (see Table 1), with continued systems (Nordström & Malmsten, 2017; Zhang et al., 2019;
effort aimed at designing peptides with improved therapeutic Zhao et al., 2016).
Table 1 Select antimicrobial peptides with potent activity against MDR pathogens
Peptide Sequence Development phase Description
LLGDFFRKSKEKIGKE- From human leucocytes, kills bacteria through pore formation and pos-
Human LL-37
FKRIVQRIKDFLRNLVPRTES sesses immunomodulation activities.
SAAP-148 (de LKRVWKRVFKLLKRY- LL-37 derivative, shows potent bactericidal activity through membrane
Preclinical
Breij et al., 2018) WRQLKKPVR permeabilization and wound healing activity.
Lysine-phenylalanine-rich peptide from snake venom. Shows potent ef-
Cathelicidin-BF KFFRKLKKSVKKRAKEFFK-
ficacy against fungal and bacterial strains including MDR pathogens.
(Wang et al., 2008) KPRVIGVSIPF
Low hemolytic activity.
D-OH-CATH30 KFFKKLKNSVKKRAKKFFK- Cathelicidin from snake venom, rapidly kills MDR gram-positive and
Preclinical
(Zhao et al., 2018) KPRVIGVSIPF gram-negative pathogens, with low hemolytic activity and in vivo toxicity.
Indolicidin Isolated from bovine leucocytes, shows potent bactericidal activity
ILPWKWPWWPWRR III
(Falla et al., 1996) through pore formation.
Omiganan (Melo & Indolicidin derivative, broad-spectrum antimicrobial activity, therapeutic
ILRWPWWPWRRK-NH2 III
Castanho, 2007) agent against acne and catheter related infections.
Ci-MAM-A24 (Fed- WRSLGRTLLRLSHALK- Isolated from Ciona intestinalis, shows potent bactericidal activity
Preclinical
ders et al., 2010) PLARRSGW-NH2 against MRSA, VRE, and MDR P. aeruginosa through pore formation.
Pexiganan GIGKFLKKAKKFGKAF- Magainin analog, phase III clinical trials for treatment of bacterial infec-
III
(Ge et al., 1999) VKILKK-NH2 tions and diabetic foot ulcers. Potent antimicrobial activity.
Thanatin derivative, shows improved antimicrobial activity with reduced
S-thanatin GSKKPVPIIYCNRRSGKC-
Preclinical hemolytic activity. Potently inhibits gram-negative growth in vitro and in
(Wu et al., 2011) QRM
vivo and alleviates sepsis in mice.
Analog of arenicin-3 with β-hairpin structure, exhibits potent microbici-
AA139 (van der GFCWYVCARRNGARVCYR-
Preclinical dal activity against MDR gram-negative pathogens, and excellent can-
Weide et al., 2019) RCN
didate for in vivo application.
Synthetic tetra-branched peptide with potent microbicidal activity
SET-M33 (Van De against MDR bacteria and in vivo therapeutic potential. Currently under
KKIRVRLSA)4K2KβΑ-ΟΗ Preclinical
Weide et al., 2019) development for treatment of sepsis and lung infections (Brunetti et al.,
2016a).
APAKCTPYCYPTHDGVFC- Cysteine-rich peptide cloned from marine fish. Potent microbicidal ac-
EC-hepcidin3 Preclinical
GVRCDFQ tivity against S. aureus and Pseudomonas spp.
Cationic β-hairpin peptide from horseshoe crab. Potent microbicidal ac-
Tachyplesin-1
KWCFRVCYRG ICYRRCR II tivity against gram-negative and gram-positive bacteria. Use limited by
(Ohta et al., 1992)
high cytotoxicity.
Cathelicidin AMPs, which are found in humans and other used as a template for the design of several synthetic
animals, are excellent candidates for therapeutic agents. They peptides with improved antibiotic activity against nosocomial
display multifunctional roles, including potent broad-spectrum pathogens, biofilms, and persister cells (Dürr et al., 2006;
antimicrobial activity against infectious agents such as fungi, Xhindoli et al., 2016). A notable LL-37 derivative (SAAP-148)
viruses, and bacteria, and can trigger specific immune designed by de Breij et al. (2018) through amino acid
responses such as activation and recruitment of immune cells substitution of the C-terminal chain of LL-37 shows potent
(Gennaro et al., 1989; Kościuczuk et al., 2012). The human microbicidal activity (minimum inhibitory concentration (MIC)
cathelicidin LL-37, expressed in various tissues and 0.4 to 12.8 µm) against several ESKAPE pathogens (e. g., E.
circulating cells, is the most extensively studied peptide and faecium, S. aureus, K. pneumoniae, A. baumannii, P.
exhibits potent bactericidal activity against bacterial strains aeruginosa, and Enterobacter species) without selection of
and fungi (Björstad et al., 2009). Furthermore, it has been resistance. This derivative can also eliminate biofilms and

persister cells of S. aureus, A. baumannii and P. aeruginosa in potent bactericidal activity through membrane
the micromolar range. permeabilization against gram-negative and gram-positive
Cathelicidins make up the bulk of naturally occurring AMPs nosocomial pathogens such as E. coli, P. aeruginosa, and S.
in snake venom. Several snake venom-based AMPs have aureus (Falla et al., 1996). Several synthesized derivates of
been established, which potently kill both fungal and bacterial indolicidin have shown improved antimicrobial activities
pathogens (Jin et al., 2016; Wang et al., 2011; Zhang, 2015). against a wide panel of MDR nosocomial pathogens with low
Zhao et al. (2018) identified a novel 34-amino acid residue MIC values, e.g., RN7-IN10 and RN7-IN9 (Jindal et al., 2015).
cathelicidin (OH-CATH) from the king cobra, with its analog D- Omiganan, a novel peptide currently under phase III clinical
OH-CATH30 found to exhibit potent microbicidal activity (MIC trials as a therapeutic agent for bacterial-caused acne and
1.56 to 12.5 µg/mL) against several gram-negative and gram- catheter-associated bloodstream infection (Melo & Castanho,
positive bacteria, including MDR A. baumannii, MDR P. 2007), also exhibits potent broad-spectrum antimicrobial
aeruginosa, MRSA, and E. coli, compared to nine commonly activity (Sader et al., 2004).
used antibiotics. Remarkably, bacteria-killing kinetics revealed Also currently under preclinical trial, Ci-MAM-A24, a
that D-OH-CATH30 rapidly killed E. coli within 6 min and synthetic peptide derivative of a peptide precursor isolated
exhibited low hemolytic activity on red blood cells at high from Ciona intestinalis, exhibits potent bactericidal activity
concentration. Furthermore, in vivo toxicity testing using mice through membrane permeabilization at low concentration (MIC
revealed a high lethal dose, with no deaths observed at high <10 µg/mL) against MDR nosocomial pathogens, including
concentrations of 160 mg/kg (Li et al., 2012; Zhao et al., MRSA, VRE, MDR P. aeruginosa, ESBL-producing E. coli
2018), thus highlighting their potential as excellent therapeutic (Fedders et al., 2010). Thus, it is an important candidate as a
candidates. therapeutic agent against MDR nosocomial pathogens. The
Cathelicidin-BF is a 30-amino acid residue cathelicidin pexiganan peptide, a synthetic 22-amino acid residue analog
isolated from the venom of Bungarus fasciatus and possesses of magainin isolated from the African clawed frog Xenopus
potent antimicrobial activity, even against MDR clinical laevis (Ge et al., 1999; Zasloff, 1987), also exhibits potent
isolates (Wang et al. 2008). Its designed and shortened 15- broad-spectrum bactericidal activity against several
amino acid residue peptide cathelicidin-BF15 also shows pathogens at low concentration. It is currently in phase III
strong efficacy against fungal species such as Candida clinical trials as an agent for diabetic foot ulcers caused by
albicans (Jin et al., 2016; Wang et al., 2008) and against bacterial infections and can rapidly kill pathogens such as P.
several bacterial strains including MDR clinical isolates of E. aeruginosa and several other gram-positive and gram-
coli, P. aeruginosa, and S. aureus through membrane negative bacteria, with a low tendency to induce resistance
permeabilization (Wang et al., 2008), with low hemolytic selection (Ge et al., 1999; Mahlapuu et al., 2016). However,
activity on red blood cells and therapeutic potential against several reports demonstrate selection of resistance to
acne vulgaris (Wang et al., 2011). pexiganan following long-term laboratory exposure of
Several AMPs with potent antimicrobial properties have also pathogens (Habets & Brockhurst, 2012; Perron et al., 2006).
been isolated from amphibians such as salamanders, frogs, Thanatin is another potential therapeutic candidate for MDR
and toads (Patocka et al., 2018; Liu et al., 2011; Xiao et al., pathogens. It is a 21-amino acid residue peptide and its
2011). Such peptides are viable targets for the development of analog, S-thanatin, exhibits low hemolytic activity and potent
therapeutic agents. For example, Qi et al., (2019) identified antimicrobial activity against several strains of gram-negative
two novel cathelicidin peptides, OL-CATH-1 and -2, from the and gram-positive bacteria (Wu et al., 2011). Furthermore,
frog Odorrana livida, which both show potent antimicrobial with improved therapeutic activity, S-thanatin shows potent
and anti-inflammatory activities. Wang et al. (2013) isolated activity against nosocomial pathogens K. pneumoniae and E.
five novel AMPs from Limnonectes kuhlii frog skin secretions, coli at very low concentrations, and can alleviate sepsis in
which exhibited potent antimicrobial activity against several mice models, thus making it an excellent therapeutic
gram-negative and gram-positive bacterial strains, but with candidate (Ding et al., 2009; Wu et al., 2013).
low hemolytic activity on mammalian cells. Colistin is an important AMP used as a last-resort drug for
Other extensively studied cathelicidins include human- β the treatment of MDR pathogen infections. Recent reports of
defensin 3 (hBD-3), sheep myeloid peptide (AMP-29), rat selection of resistance to colistin thus present a concerning
cathelin-related antimicrobial peptide (rCRAMP), and bovine global healthcare predicament in the fight against MDR
myeloid antimicrobial peptide 27 (BMAP-27), which bacterial infections (Falagas et al., 2005; MacNair et al., 2018;
demonstrate potent microbicidal activity against pathogenic Yamamoto et al., 2018). Remarkably, two novel AMPs (AA139
strains such as E. coli, P. aeruginosa, MRSA, and A. and SET-M33) with similar MOA as colistin are currently in
baumannii, inhibition of biofilm formation, and development and have shown excellent therapeutic potential
immunomodulation activity (Dhople et al., 2006; Giacometti et both in vitro against several MDR gram-pathogens and in-vivo
al., 2004; Guo et al., 2018; Kościuczuk et al., 2012; Kurosaka in animal disease models (van der Weide et al., 2019). AA139
et al., 2005). is a 21-amino acid amphipathic peptide with reduced cytotoxic
Besides cathelicidins, other AMPs with diverse structural and hemolytic activity. It was designed from arenicin-3, a
scaffolds and properties have been reported. Indolicidin, a peptide with potent microbicidal activity against several MDR
natural cationic peptide from bovine neutrophils, also exhibits bacterial strains and isolated from the marine lugworm
Arenicola marina (Sierra et al., 2017; Wang et al., 2018). SET- utilization and approval as antibiotic alternatives (Falanga et
M33 is a synthetic AMP exhibiting potent microbicidal activity al., 2016; Lombardi et al., 2019; Wang et al., 2016). The main
against gram-negative bacteria through membrane disruption factor limiting the systemic application of AMPs is their
and an excellent candidate for in vivo application, as sensitivity to proteolytic digestion. For instance, host
evidenced from animal models of infectious diseases having proteolytic enzymes in intestinal mucosa, gastrointestinal
both anti-inflammatory and immunomodulatory activities tract, and blood plasma can readily degrade antimicrobial
(Brunetti et al., 2016b; Falciani et al., 2012; van der Weide et peptides, which negatively impacts their in vivo stability and
al., 2017). pharmacokinetics (Moncla et al., 2011; Starr & Wimley, 2017).
Several AMPs with potent activity against gram-positive and Therefore, as a result, many AMPs are limited to topical
gram-negative MDR and showing excellent prospects as application rather than oral or intravenous administration.
therapeutic agents have also been isolated and characterized Moreover, studies have demonstrated that, as a defensive
from marine animals (Destoumieux-Garzón et al., 2016; Tincu mechanism in the presence of AMPs, certain bacteria will up-
& Taylor., 2004). For example, mytimacin-AF, an 80-cysteine- regulate the secretion of proteolytic enzymes and
rich amino acid residue isolated from marine mollusks, shows metalloproteases (MMPs) that can partially or completely
potent activity against both gram-positive and gram-negative degrade AMPs (Lai et al., 2007; Sieprawska-Lupa et al.,
bacteria, especially against nosocomial pathogens S. aureus 2004).
and K. pneumoniae (MIC<2 μg/mL) (Zhong et al., 2013). EC- Toxicity and efficacy of AMPs is another major drawback of
hepcidin3, cloned from marine fish Epinephelus coioides, is a their use. Several AMPs have adverse side effects in vivo,
novel cysteine-rich AMP with rapid and potent microbicidal which limits their use to topical application only (McPhee &
activity against S. aureus and Pseudomonasstutzeri (MIC< Hancock, 2005). Moreover, in addition to the low correlation
3 μmol/L) (Qu et al., 2013). Tachyplesins, a class of peptides between in vitro- and in vivo-based results in some cases,
isolated from horseshoe crab hemocytes, are cationic β- physiological conditions such as high salt concentration and
hairpin structured peptides with potent antimicrobial activities serum components can negatively affect the antimicrobial
against MDR gram-negative and gram-positive bacteria at low activity of many AMPs (Cantisani et al., 2014; de Breij et al.,
concentrations (Falanga et al., 2016; Liu et al., 2018; 2018; Han et al., 2016). For most AMPs, antimicrobial activity
Nakamura et al., 1988), although with increasing hemolytic is dependent on the electrostatic interactions between
and cytotoxic activity at higher levels (Edwards et al., 2017; positively charged peptides and negatively charged plasma
Liu et al., 2018; Ohta et al., 1992). membranes (Guilhelmelli et al., 2013). Such interactions can
Continued research on AMPs has yielded a new class of be affected by elevated salt levels or binding of AMPs to
highly potent peptides called "Selectively Targeted AMPs" serum components (e. g., lipoproteins) (Li et al., 2017).
(STAMPs), which demonstrate increased sensitivity to target Therefore, efficacy screening of AMPs under different
pathogens without harming normal flora and increased physiological conditions and in the presence of host
bacterial killing potency and kinetics (Chung & Khanum, components is necessary to affirm their activity.
2017). Such AMPs have been designed to target pathogens Compared to conventional antibiotics, AMPs are also
through specific determinants followed by selective killing expensive to produce. Therefore, current efforts are being
(Sarma et al., 2018). Notable STAMPs include synthetic directed at designing shorter peptides with reduced side
peptide M8(KH) -20, a multi-headed peptide specifically effects and improved stability under different physiological
targeting and potently killing P. aeruginosa and Streptococcus conditions (Kim et al., 2013; Zhao et al., 2015). For example,
mutans in vitro with very little effect on other pathogens (He et Li et al. (2017) pioneered an important strategy for designing
al., 2009). Oritavancin, another synthetic STAMP designed AMPs with trypsin inhibitor activity based on a peptide isolated
from the naturally occurring glycopeptide chloroeremoycin and from the frog Odorrana grahami.
currently in clinical development, is reported to be highly Although AMPs have a low likelihood to select for
selective and potently kills MDR pathogens such as methicillin- resistance, reports already exist detailing the development of
resistant S. aureus and vancomycin-resistant S. aureus resistance against some AMPs (Andersson et al., 2016;
(VRSA) more rapidly than vancomycin through membrane Omardien et al., 2016); for example, the development of
permeabilization and inhibition of cell wall synthesis (Allen & resistance to colistin by A. baumannii following long-term
Nicas, 2003; Chung & Khanum, 2017). clinical application (Jeannot et al., 2017; Liu et al., 2016).
Colistin is a last-resort drug used for the treatment of MDR
nosocomial pathogens, and thus resistance to colistin is an
CHALLENGES FACING EXPLOITATION OF AMPs AS important clinical issue (Liu et al., 2016; MacNair et al., 2018;
THERAPEUTIC AGENTS AND SOLUTION STRATEGIES Paterson & Harris., 2016). Several mechanisms have been
reported to be responsible for resistance to AMPs, including
To be considered for approval as a therapeutic agent, effective expression of efflux pumps, surface charge modification to
AMPs need to show broad-spectrum activity, high selectivity impede membrane-peptide electrostatic interactions, and
for bacterial pathogens, and low cytotoxicity on mammalian increased secretion of proteolytic enzymes (Andersson et al.,
cells (Dathe & Wieprecht, 1999). Currently, various AMPs are 2016; Bechinger & Gorr, 2017; Morita et al., 2012). For
under clinical trial; however, several factors curtail their full example, S. aureus can alter surface charge by adding basic

amino groups from D-alanine from the cytoplasm to teichoic activity and reduced cytotoxicity. Such efforts are bearing fruit,
acid on the membrane surface (Peschel et al., 1999). as evidenced in the presence of short synthetic AMPs with
Resistance to AMPs also raises other critical issues such as potent and rapid microbicidal activity against several MDR
the potential development of cross-resistance to antibiotic pathogens, even those showing resistance to last-resort
regimens and host AMPs (Conlon, 2015; Kubicek-Sutherland drugs, thus presenting hope in the war against multidrug
et al., 2017), which could create unprecedented detrimental resistance.
consequences.
Presently, studies are focusing on developing strategies to COMPETING INTERESTS
improve the efficacy of AMPs in vivo, enhance selectivity for
microbial cells while reducing cytotoxicity, increase stability, The authors declare that they have no competing interests.
and minimize proteolytic degradation. Chemical modifications
such as the addition of D-amino acids, cyclization, or AUTHORS' CONTRIBUTIONS
acetylation are important strategies used to improve the
stability of AMPs and reduce sensitivity to proteolytic J. M., X. H., R. L., and Y. Z. Z. conceived the review and prepared the
degradation (Gao et al., 2018; Zhao et al., 2016). However, manuscript. All authors contributed to the discussions. All authors read and
additional modifications add to production costs. To solve this, approved the final version of the manuscript.
efforts are currently being directed at the design and synthesis
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ZOOLOGICAL RESEARCH

Antimicrobial peptides: new hope in the war against

ABSTRACT killing action, broad-spectrum activity, and

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