1 s2.0 S1368764623000377 Main

Drug Resistance Updates 68 (2023) 100954
Contents lists available at ScienceDirect
Drug Resistance Updates

journal homepage: www.elsevier.com/locate/drup
Antimicrobial peptides for combating drug-resistant bacterial infections

Jiaqi Xuan a, b, 1, Weiguo Feng c, 1, Jiaye Wang a, Ruichen Wang a, Bowen Zhang a, Letao Bo d,
Zhe-Sheng Chen d, *, Hui Yang a, *, Leming Sun a, b, **
a
School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in
Special Environment, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China
b
Innovation Center NPU Chongqing, Northwestern Polytechnical University, Chongqing 400000, China
c
School of Life Science and Technology, Weifang Medical University, Weifang 261053, Shandong, China
d
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
A R T I C L E I N F O A B S T R A C T
Keywords: The problem of drug resistance due to long-term use of antibiotics has been a concern for years. As this problem
Antimicrobial peptides grows worse, infections caused by multiple bacteria are expanding rapidly and are extremely detrimental to
Drug resistance human health. Antimicrobial peptides (AMPs) are a good alternative to current antimicrobials with potent
Antibiotics
antimicrobial activity and unique antimicrobial mechanisms, which have advantages over traditional antibiotics
Bacterial infection
in fighting against drug-resistant bacterial infections. Currently, researchers have conducted clinical in
vestigations on AMPs for drug-resistant bacterial infections while integrating new technologies in the develop
ment of AMPs, such as changing amino acid structure of AMPs and using different delivery methods for AMPs.
This article introduces the basic properties of AMPs, deliberates the mechanism of drug resistance in bacteria and
the therapeutic mechanism of AMPs. The current disadvantages and advances of AMPs in combating drug-
resistant bacterial infections are also discussed. This article provides important insights into the research and
clinical application of new AMPs for drug-resistant bacterial infections.
1. Introduction used in combination with emerging technologies (Wu et al., 2018). As

AMPs can be electrostatically adsorbed on the surface of bacterial
Bacterial antimicrobial resistance (AMR) refers to the insensitivity of membranes and are usually hydrophobic, they can easily penetrate and
bacteria to antibiotic treatment, which is one of the leading public destroy the membrane structure, resulting in cell death. AMPs also play
health threats of the 21st century (YJ et al., 2005). It is reported that in important roles in the host’s innate immune defense system. Unlike
less than 30 years, AMR may be more deadly than cancer and will kill 10 traditional antibiotics with only one target, AMPs can destroy pathogens
million people a year by 2050 (Murray et al., 2022). As bacterial drug at multiple targets, greatly reducing the emergence of drug-resistant
resistance becomes more common, the prevention and treatment of bacteria. They have broad-spectrum antibacterial properties and are
drug-resistant bacterial infections become more critical. Although an currently being used in clinical treatment of pathogen infection, wound
tibiotics used to be able to treat most bacterial infections, the emergence healing and cancer. Overall, they will be one of the promising substitutes
of AMR weakens the effectiveness of existing antibiotics. Therefore, it is for antibiotics in the future (Mallapragada et al., 2017; T et al., 2017).
important to find effective alternatives. At present, antimicrobial pep This article reviews the emergency of drug resistance in bacteria, the
tides (AMPs) have become a promising antimicrobial strategy because of basic structure, synthesis, the therapeutic mechanisms of AMPs, and
their broad-spectrum activity, strong effect on gram-negative bacteria some current advances in AMPs for the treatment of drug-resistant
and few drug resistance (Huang et al., 2010). bacterial infections. Additionally, some challenges encountered by
Previous studies have discovered that AMPs have certain effects on AMPs and the application prospect of AMPs in combination with
drug-resistant bacteria infection, and they may play better roles when advanced new technologies are also discussed (Fig. 1).
* Corresponding authors.
** Corresponding author at: School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Pro
tection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Shaanxi, Xi’an 710072, China.
E-mail addresses: chenz@stjohns.edu (Z.-S. Chen), kittyyh@nwpu.edu.cn (H. Yang), lmsun@nwpu.edu.cn (L. Sun).
1
These authors contributed equally.
https://doi.org/10.1016/j.drup.2023.100954
Received 11 January 2023; Received in revised form 21 February 2023; Accepted 27 February 2023
Available online 1 March 2023
1368-7646/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
J. Xuan et al. Drug Resistance Updates 68 (2023) 100954
2. Generation of drug resistance in bacteria 2.1.2. Extended spectrum β-lactamases (ESBLs)

ESBLs are β-lactamases characterized by inactivating narrow-
Drug resistance in bacteria is mainly divided into two kinds: inherent spectrum and broad-spectrum cephalosporins, monocyclic antibiotics
resistance and acquired resistance. The inherent resistance is referred to and anti-gram-negative bacilli penicillin. It can reduce the effect of an
bacteria that is insensitive to certain antibiotics. It is commonly medi tibiotics by changing binding targets of various antibiotics (Kitano et al.,
ated by chromosome resistant genes, which does not change generally. 2020). ESBLs are the gene mutation products of the common β-lacta
Acquired resistance refers to certain kinds of bacteria that change their mase, and the drug resistance is mediated by plasmids. The resistance
metabolic pathway to ensure that they are not killed by antibiotics rate of ESBLs strains to aminoglycosides and quinolone antibiotics is
(Fig. 2). Acquired resistance of the drug-resistant bacteria can be ob about 60%. The most important resistance mechanism of Enterobacteri
tained through gene mutation. Moreover, these bacteria can be used to aceae bacteria, the most important pathogenic bacteria such as Escher
generate multiple drug resistance through the passage, transfer, and ichia coli and Klebsiella pneumoniae in clinical bacterial infectious
variation of drug-resistant genes. diseases, is the production of ESBLs mediated by plasmids (Stewart
et al., 2021).
2.1. Bacteria produce antibiotic-inactivating enzymes
2.1.3. Aminoglycoside modifying enzyme
2.1.1. β-lactamase The most important mechanism of bacterial resistance to the ami
All β-lactam antibiotics have a core β-lactam ring, which can bind to noglycoside antibiotics is producing the plasmid-mediated amino
the penicillin-binding protein (PBP) of bacteria to inhibit the synthesis glycoside modifying enzyme (Yohei and Yoshichika, 2007).
of the bacterial cell wall and induce elimination of bacteria. However, Enzymatically modified aminoglycoside antibiotics can’t interact with
the β-lactamase produced by bacteria can bind to the β-lactam ring and ribosomal target sites and lose their antibacterial activity. These en
open the β-lactam ring, which can cause drug inactivation. The metal- zymes can be divided into acetyltransferase (AAC), phosphotransferase
β-lactamolytic enzyme produced by the super bacteria NDM-1 (New (APH), and nucleoside transferase (ANT). Currently, more and more
Delhi metal-β-lactamase-1) present in earlier years can resolve the strains could produce two or more enzymes that have the ability to
β-lactam ring. This enzyme can resist any antibiotic containing the counteract against aminoglycoside antibiotics. For example, Pseudo
β-lactam ring. It was also found that the gene blaNDM-1, which encodes monas aeruginosa, which often causes infections of respiratory tract,
the enzyme, not only presents on individual plasmid but also is easy to urinary system, skin, and soft tissues, can produce at least ten passiv
transfer and recombination occurs between bacteria (Kumarasamy, ation enzymes to achieve a high degree of resistance to aminoglycoside
2010). antibiotics (Keith, 2005).
Fig. 1. Schematic diagram of AMPs in

combating against drug-resistant bacterial in
fections. (A) The structure and classification of
AMPs. (B) Representative synthesis methods of
AMPs, including ribosomal synthesis, non-
ribosomal synthesis, and chemical synthesis.
(C) The mechanisms of the generation of drug
resistance in bacteria. (D) The mechanisms of
AMPs for the treatment of drug-resistant bac
terial infections. (E) Examples of current ad
vances in AMPs for the treatment of drug-
resistant bacterial infections. (F) Some current
disadvantages of AMPs in combating drug-
resistant bacterial infections. (G) New ap
proaches and strategies available for the treat
ment of drug-resistant bacterial infections.
2
Fig. 2. Schematic representation of the mechanisms of

drug resistance in bacteria. ①Bacteria produce antibiotic-
inactivating enzymes, which causes inactivation of antibi
otics entering the cells to achieve drug resistance; ②The
structure of the target site is altered so that the drug cannot
work; ③Bacteria exert antibacterial effects by using cell
wall barriers or changing cell membrane permeability that
prevent antibiotics from entering cells or reduce the
amount of drugs available; ④Bacteria use active efflux
pumps to discharge drugs to reduce drug concentration.
2.2. Altering target site of drug action also present on the outer membrane of such bacteria, which can form
specific channels (OprD) and non-specific channels (OprF) to serve as
2.2.1. Alterations in penicillin-binding proteins (PBPs) cause β-lactam channels for nutrients and hydrophilic antibacterial drugs. Bacteria can
antibiotic resistance develop drug resistance when they lose a specific porin due to gene
PBPs catalyze the synthesis of peptidoglycan, which is the main mutation. In addition, the absence of the outer membrane protein OprF
component of the bacterial cell wall. The two catalytic functional zones makes it difficult to pass through and develop drug resistance. For
of PBPs represent glycosyltransferase and transpeptidase. The trans example, the deletion of Pseudomonas aeruginosa-specific porin OprD2
peptidase is the target site of β-lactam antibiotics. Therefore, when causes carbapenem antibiotic resistance (Karen and A, 2020).
mutations occur in PBPs, the affinity for antibiotics will be reduced,
which leads to drug resistance in the bacteria. For instance, when 2.4. Antibiotic active efflux pump
methicillin-resistant Staphylococcus aureus (MRSA) produces a special
penicillin binding protein PBP2a, it reduces their affinity with β-lactam Recently, numerous studies have proved that chromosome-mediated
antibiotics, and leads to the bacteria resistant to β-lactam antibiotics multidrug-resistant (MDR) bacteria can expel drugs from cells through
(Maria, 2018). energy-dependent active efflux pumps (Du et al., 2018; Uddin and Ahn,
2018; Huang et al., 2022). At present, there are five main types of efflux
2.2.2. Alterations in DNA topoisomerases cause quinolone antibiotic pump systems related to MDR bacteria: (1) ATP-binding cassettes
resistance transporters; (2) Major facilitator super family; (3) Small multidrug
Quinolones mainly inhibit the synthesis of DNA by inhibiting DNA resistance; (4) Multidrug and toxic compound extrusion; (5)
topoisomerase to achieve bacteriostatic effect. The DNA helicase Resistance-Nodulation-Division family. Among the above transporters,
(GyrA2B2) and topoisomerase IV (ParC2E2) of bacteria are the targets of except ATP binding cassette transporters, which use ATP as energy for
quinolones. After the mutation of their encoding genes, the structure of drug efflux, other transporters use proton driving force as energy and
DNA helicase or topoisomerase changes, which results in a decreased form reversal transporters of protons and drugs. During the transport
affinity between the drug and DNA-enzyme complex, causing drug process of proton and drug, protons enter cells and the drug is dis
resistance (T and H, 2001). Quinolone resistance is mainly caused by charged out of cells. Currently, common examples of active efflux pumps
point mutations in chromosomal topoisomerase genes. The frequency of are the AcrAB-TolC efflux system of Escherichia coli, and the
spontaneous single-gene mutations ranging from 10 to 6–10–10, causing MexAB-OprM efflux system of Pseudomonas aeruginosa (Horna et al.,
different degrees of bacterial resistance to quinolones, usually with a 2018; Shiela et al., 2019). The substrates of these two efflux pumps are
low degree of resistance. A high degree of drug resistance requires a mainly antibiotics, but also include some oxidants and organic solvents.
double mutation in the chromosomal topoisomerase gene with a fre
quency of 10–14–10–16. Therefore, the proportion of quinolone resis 3. Structure and classification of AMPs
tant bacteria acquired through genetic mutations is not large.
Based on the presence or absence of two key secondary structure
2.3. Alteration of cell wall or outer membrane permeabilization barrier components, α-helix and β-sheet, AMPs are usually classified into four
families, including linear α-helix peptides, β-sheet peptides, peptides
Bacteria can counteract antibacterial effects by using cell wall bar with both α-helix and β-sheet, and peptides without α-helix or β-sheet
riers or changing membrane permeability so that antibiotics cannot (Hancock and Sahl, 2006). In addition to these four categories, a fifth
enter cells or reach target sites, which is a defense mechanism formed by family referred to as the topologically complex AMPs has recently been
bacteria during evolution. This mechanism of drug resistance is mainly added (Mura et al., 2016).
present in gram-negative bacteria. Because gram-negative bacteria are
surrounded by an outer membrane barrier, which is consist of proteins 3.1. The α-helix structure
(including membrane porins), lipopolysaccharide (LPS), and phospho
lipids. The outer membrane barrier and the drug active efflux pump The α-helix conformational peptides are a relatively diverse and
work synergistically to mediate the inherent resistance of bacteria, well-studied group of AMPs, with hundreds of different sequences
because they can reduce the amount of drug reaching the target site already identified from natural sources (Porcelli et al., 2013). They
(Hiroshi, 2003). In addition, the porous proteins OmpF and OmpC are generally consist of 12–40 amino acid residues, rich in helix-stabilizing
3
residues like Ala, Leu, and Lys. (Takahashi et al., 2010). A representative food industry. For example, sheep thiopeptide Nisin is a typical
example is Magainin-2, a family of peptides with broad-spectrum anti ribosome-synthesized AMPs, which has been used as food preservative
microbial activity isolated from the skin of Xenopus laevis (Zasloff, for more than 40 years (Nes, 1997).
1987).
4.2. Non-ribosomal synthesis of AMPs
3.2. The β-sheet structure
Besides ribosomal synthesis, there is another way to form amide
AMPs in the β-family have at least one pair of two β-strands. The bond in nature, which is called non-ribosomal synthesis (Lovering et al.,
reason this group of AMPs are structurally stable is that almost all of 2012). Non-ribosomal synthetic peptides (NRPs) are synthesized with
them contain cysteine residues, which form one or more disulfide bonds the participation of non-ribosomal peptide synthetase without the help
(Nguyen et al., 2011). As a result, these peptides are more stable in of ribosomes and messenger RNA (Gan et al., 2021). This kind of AMPs
solution and do not produce major structural changes in the membrane are often used as systemic and local antibacterial drugs, and also have
environment. Some representative examples of AMPs with the β-sheet anti-tumor and anti-fungal applications. They also have a wide range of
structure are bovine lactoferrin, human defensin, and so on (Deshayes biological activities in the synthesis of animal feed additives and the
et al., 2021). inhibition of nucleotide synthesis (Erica S. L., 2006). Vancomycin is a
very typical non-ribosomal synthetic tricyclic glycopeptide (Mermer
3.3. The structure of both α-helix and β-sheet et al., 2020). It can interfere with the peptidoglycan in the cell wall
structure of bacteria to interfere with cell wall synthesis, and then kill
AMPs containing both α-helix and β-sheet elements are found not bacteria by inhibiting the growth and reproduction of bacteria.
only in humans and other mammals, but have also been described in
various invertebrates and plants (Wang and Guangshun, 2014). The 4.3. Chemical synthesis of AMPs
classification of this kind of AMPs is based on the different arrangements
of their three to five disulfide bonds, such as the cis defensins super Early discoveries of AMPs relied on isolation from natural sources,
family (J and DJ, 2019). often requiring large amounts of biological feedstock from which only
small amounts of pure peptides could be extracted. Currently, AMPs can
3.4. The structure without α-helix and β-sheet be obtained on a large scale by chemical synthesis.
Some AMPs do not adopt any specific 3D structure in solution or in 4.3.1. Solid phase peptide synthesis (SPPS)
contact with membranes, and are therefore referred to as extended SPPS, originally introduced by Merrifield (Merrifield, 1963), which
linear structures. These peptides lack α-helices and β-sheets and are involves the attachment of the C-terminal amino acids of AMPs to a
usually enriched amino acid, generally glycine, proline, tryptophan or polymeric solid carrier. Typically, through cleavable chemical linkers,
histidine (J and DJ, 2019). Since there are less than 400 known 3D the amino acid building blocks are successively deprotected and coupled
structures of this family out of more than 2600 identified AMPs, this to an achieve peptide chain extension, providing the desired peptide in
classification system is considered as an ad-hoc approach (Wang, 2015). high yield and purity. In this process, each amino acid is added
sequentially during SPPS, thus making it possible to modulate and
3.5. The topologically complex AMPs improve antimicrobial potency and to study structure-activity relation
ships (Palomo, 2014). It also eliminates the need for isolation of in
A recent fifth group of AMPs has been proposed for AMPs with cyclic termediates, thus allowing for shorter production cycles and having the
and complex topologies. These peptides do not adopt a linear structure, advantage of greater automation and scalability (Ramesh et al., 2017).
unlike AMPs belonging to those four classes, but with “head to tail” and
“head to side chain” cyclic topologies. To stabilize their structure, most 4.3.2. Microwave assisted synthesis
of the cyclic AMPs contain disulfide bonds or thioether bridges (Shafee The bottleneck in peptide synthesis has been the purification step,
et al., 2017). hence the increasing demand for high quality peptides. The growing
popularity of microwave-assisted peptide synthesis technology com
4. Synthesis of AMPs bined with low-cost reagents addressed this problem (Pedersen et al.,
2012). Microwave heating is often applied to the coupling and depro
The synthesis of AMPs can be broadly classified into ribosomal tection steps, which can significantly reduce the reaction time and
synthesis, non-ribosomal synthesis, and chemical synthesis. improve the purity of the crude peptide extracts.
4.1. Ribosomal synthesis of AMPs 5. Mechanisms of AMPs for the treatment of drug-resistant
bacterial infections
Ribosomal synthesis is the basic process of peptide and protein
synthesis. AMPs synthesized by ribosomes are usually derived from a As a result of antibiotic abuse, MDR bacteria have emerged. Among
relatively short sequence of precursor peptides in a process that requires them, MRSA, vancomycin-resistant Enterococcus (VRE), multidrug-
at least one active proteolytic. Different proteolytic enzymes participate resistant Pseudomonas aeruginosa (MDR-PA), and multidrug-resistant
the generation of peptides of different lengths with different antimi Acinetobacter baumannii (MDR-AB) are commonly seen in clinics. With
crobial and immunomodulatory properties (Sieprawska-Lupa et al., the failure of antibiotics treatment, how to prevent and treat bacterial
2004). In bacteria, genes encoding prepropeptides are usually clustered infections has become a persistent topic. In recent years, AMPs have
with genes encoding proteins that modify the prepropeptide, and genes been considered as a substitute for antibiotics due to their unique anti
that are resistant to AMPs (Mcintosh et al., 2009). Once translation oc bacterial mechanism and complex antibacterial effect, which opens a
curs at the ribosome, some peptides undergo further post-ribosomal new prospect for the response to multi-resistant bacteria (Hancock and
peptide synthesis and these peptides synthesized and Sahl, 2006). Compared with antibiotics, biopeptides can act on bacterial
post-translationally modified by ribosomes are considered to be an un membranes or other targets. Additionally, the probability of drug
explored source of antimicrobial drugs (Yang and Donk, 2014; BH et al., resistance to peptides generated by gene mutation is low, therefore, drug
2021). Some of the ribosome-synthesized AMPs are currently undergo resistance is more difficult to develop in AMPs than antibiotics (Peschel
ing clinical trials, and there are a few applications in agriculture and and Sahl, 2006). These factors demonstrate that AMPs can be used as an
4
epistatic substitute for antibiotics. The mechanisms of AMPs for the formed, new bacteria will be continuously sowed and spread, resulting
treatment of drug-resistant bacterial infections can be summarized as in chronic infection, which is difficult to cure (Archer et al., 2011). By
biofilm permeation (Figs. 3a, 3b), re-sensitization, intracellular bacte disrupting the biofilm structure through the membrane permeation
riostatic function (Fig. 3c), immune activity regulation and biofilm mechanism, the effective inhibition of AMPs on Staphylococcus aureus
inhibition. infection can be achieved. When antibiotics are utilized to deal with
Staphylococcus aureus, the polysaccharide structure on the biofilm will
hinder its penetration into the bacteria, reducing the targeting effect of
5.1. Biofilm permeation mechanism antibiotics, which is one of the reasons for the failure of most antibiotic
treatment (Mah and O’Toole, 2001). The feasibility and importance of
Previous studies have shown that membrane permeation was the AMPs as an alternative to antibiotics were discussed here. Since bacteria
main mechanism for the antibacterial effect of AMPs, and research in grow dormant in the cell membrane, most conventional antibiotics are
this area was relatively mature. Cationic charge and hydrophobic resi helpless against the 48-hour-old mature cell membrane (Wolcott et al.,
dues are considered as the two main physical characteristics of AMPs. 2010). However, researchers have synthesized a novel short-chain
The presence of a net positive charge enhances the interaction of peptide and tested it for biofilm inhibition of Staphylococcus aureus.
cationic AMPs with negatively charged cytoplasmic membranes. This AMP showed a strong inhibition of Staphylococcus aureus biofilm
Meanwhile, other bacterial targets with hydrophobic residues promote formation and was superior to vancomycin and linezolid at the same
the interaction with the fatty acyl chain (Nguyen et al., 2011), which concentrations (Mohamed et al., 2016).
implement the membrane insertion of AMPs. Permeation of biofilm
takes place with three driving forces: net positive charge, hydrophobic
group, and selective transmittance of membrane (allowing peptides to 5.2. Re-sensitization mechanism
enter the cell from the solution) (Jenssen et al., 2006). The electrostatic
bonds between cationic peptides and negatively charged components on The existence of AMPs opens up a completely new possibility in
the external bacterial envelope attract each other. Eventually, the pep dealing with vancomycin-resistant Staphylococcus aureus (VRSA).
tide reaches the surface of the cell membrane, and realizes membrane Studies have shown that peptides at sub-inhibitory concentrations can
permeation through several hypothetical models, such as barrel plate achieve the re-sensitization of VRSA to some conventional antibiotics,
model, carpet model, annual pore model, aggregation channel model with the potential to inhibit the development of drug resistance (Mar
and sinking raft model. The latest research shows that AMPs can also tinez et al., 2019). Regarding the mechanism of re-sensitization, re
degrade cell membrane through some unclear mechanisms. The five searchers proposed that the stable osmosis of peptides at sub-inhibitory
main hypothesized mechanisms are: interruption of quorum sensing, concentration might be beneficial to improving the permeability of
destruction of biological membrane potential, inhibition of alarm sys bacterial membrane and enabling antibiotics to reach targets with high
tem, degradation of biofilm matrix and polysaccharides, and inhibition probability. Previous studies showed that the human milk protein-lipoid
of expression of transporters (Yasir et al., 2018). complex HAMLET (Human α-lactalbumin made lethal to tumor cells)
The formation of biofilm is considered to be one of the factors desensitizes MRSA to methicillin and VRSA to vancomycin by depolar
contributing to the toxicity of Staphylococcus aureus. After the biofilm is ization of the bacterial membrane and the dissipation of proton
Fig. 3. Overview of the mechanism of AMPs in

inhibiting MDR bacteria. (a) There are differ
ences in the membrane cleavage mechanisms
between gram-positive(A) and gram-negative
(B) bacteria. (b) Four commonly accepted hy
potheses of membrane cracking mechanisms:
carpet model(i), bucket plate model(ii), annular
hole model(iii) and aggregation model(iv). (c)
The physiological process and target of AMPs in
drug-resistant bacteria (taking gram-negative
bacteria as an example): ①The physiological
process of DNA, such as DNA response, tran
scription and replication. ②RNA-related syn
thesis and metabolism. ③Biosynthesis and
folding process of protein and regulation of
protease activity. ④Target the outer membrane
and act on peptidoglycan of biological cell wall.
⑤Affect the process of bacterial division.
5
dynamics (Marks et al., 2012). Another interesting example is the 6.1. AMPs proven to have therapeutic effects on drug-resistant bacteria
antibiotic-1b (1− 18), which was found to re-sensitize MDR Escherichia
coli to antibiotics when its utilization was below inhibitory concentra 6.1.1. Resistance of MRSA infections
tions (Marcellini et al., 2009). Through similar studies as described MRSA first appeared 60 years ago. Since then, MRSA infection has
above, researchers summarized the mechanism of re-sensitization as the spread rapidly around the world (Jacobs, 1999). Cbf-K16, an AMP
instantaneous depolarization of membrane potential at sub-inhibitory similar to enterotoxin, is a variant of bf-30 and is found in the venom of
concentration, which may be applicable to the explanation of Golden Ring Snake (Diene et al., 2011). Previous studies have found that
re-sensitization of VRSA (Goldberg et al., 2013). Cbf-K16, which is composed of 30 amino acids, has extensive antibac
terial activity and low cytotoxicity. It also has effective bactericidal
5.3. Intracellular bacteriostatic function activity against MRSA (Li et al., 2016).
Additionally, Ib-AMP4 is a plant defense AMP extracted from
As many researches have shown, AMPs can act on many physiolog impatiens seeds (Fca et al., 2019). It has significant bactericidal activity
ical processes of cells, such as DNA and protein synthesis, protein against gram-positive and gram-negative bacteria. Sadelaji et al. studied
folding, enzyme activity and cell wall synthesis (Nicolas, 2009). This the antibacterial efficiency of Ib-AMP4 in eliminating MRSA bacterial
feature shows us the possibility of AMPs replacing traditional antibiotics infection in vitro and in vivo. Their assay results confirmed the antibac
to exert antibacterial effect and thus avoid drug resistance. The unique terial activity of Ib-AMP4 to MRSA, and the SEM (Scanning Electron
effect of AMPs containing Trp on the MDR-PA has attracted people’s Microscope) results showed that Ib-AMP4 could destroy the biofilm of
attention recently. Relevant experimental results confirmed that these MRSA. The time-killing curve and growth kinetics also showed that
peptides can specifically bind to genomic DNA in MRPA0108, which Ib-AMP4 had rapid antibacterial activity. In addition, Ib-AMP4 showed
causes the double helix structure to become loose, exhibiting an anti significant therapeutic ability in the mouse model, and all mice infected
bacterial effect (Han et al., 2021). In another case, researchers found a by Ib-AMP4 protein survived, with no traces of bacteria in blood samples
new mutant peptide, Tridecaptin M, from mud bacteria, which can resist (Sadelaji et al., 2022). These results suggest that Ib-AMP4 has antibac
MDR Escherichia coli and Klebsiella pneumoniae. Tridecaptin M could terial potential and can be utilized to effectively treat MRSA infection.
affect the proton kinetics in the process of ATP synthesis of bacteria, thus
showing strong antibacterial activity (Jangra et al., 2019). 6.1.2. Resistance of MDR bacterial infections
MDR refers to the simultaneous development of resistance to mul
5.4. Immune activity regulation tiple commonly used antimicrobials, and the high frequency of the
appearance of MDR bacteria strains means that we can no longer rely on
AMPs are first found in some organisms, that are named host defense the antimicrobials of the past (Fernandez et al., 2016). Therefore,
peptides (HDPs), and act as an important part of the innate immune treatment for MDR bacterial infections is a major problem today.
system. Many AMPs can neutralize cellular endotoxin, thus enhancing Pseudin-2 (PSE-T2), a 24-amino acid AMP isolated from frog skin,
innate immunity to exert antibacterial effects. Fowlicidin-1, a host de has strong growth inhibitory activity against gram-negative bacilli
fense peptide that stimulates innate and adaptive immunity, and its (Olson et al., 2001). Kang et al. found that PSE-T2 has a significant
analogues protect mice from MRSA infection in animal experiments inhibitory effect on biofilm formation of Escherichia coli, Pseudomonas
(Bommineni et al., 2010). In addition, human LL-37, chicken CATH-2 aeruginosa, Staphylococcus aureus and their MDR strains. The inhibitory
and bovine-derived IDR-1018 are of interest. They regulate immune rate of Pseudomonas aeruginosa 4891, Escherichia coli CCARM 1238 and
cytokines by stimulating chemokine release and inhibiting Staphylococcus aureus CCARM 3090 was 97%, 89.8% and 94.2%,
LPS-mediated infection (Coorens et al., 2017). As a common opportu respectively (Kang et al., 2018). Taking Pseudomonas aeruginosa as an
nistic pathogen, Pseudomonas aeruginosa has natural resistance to example, their experimental results showed that wounds infected with
semi-synthetic penicillin, cephalosporins, carbapenems, aminoglyco MDR Pseudomonas aeruginosa healed significantly faster after PSE-T2
sides and other drugs. However, researches showed that cathelicidin BF treatment than untreated wounds or ciprofloxacin-treated wounds.
has immunomodulatory activity against Pseudomonas aeruginosa, WLBU2 is an engineered cationic peptide that contains 24 amino
resulting in significant relief of the pneumonia symptoms caused by it acids including 13 arginine. It has a strong antibacterial effect on the
(Liu et al., 2018). biofilm of MDR Acinetobacter baumannii and Klebsiella pneumoniae
(Swedan et al., 2019, Elsalem et al., 2022). Researchers showed that the
5.5. Inhibition of biofilm minimum inhibitory concentration (MIC) of WLBU2 against both
gram-negative and gram-positive bacteria was ≤ 10 μM, including
At present, it is recognized that some AMPs can inhibit the attach MRSA, vancomycin-resistant Enterococci and others. Moreover, the MIC
ment of free cells to the biofilm, by changing the morphology of free of WLBU2 against extensively-drug resistant (XDR) Acinetobacter bau
cells. Another known mechanism is that AMPs destroy quorum sensing mannii and XDR Klebsiella pneumoniae was 1.5–3.2 μM and 2.9–4.7 μM,
by reducing the expression of related genes, which directly affect the respectively. It is suggested that WLBU2 has great potential for the
biofilm formation (Luo and Song, 2021). For a number of bacteria rep clearance of MDR strains.
resented by MDR-PA, the formation of biofilm is the key factor causing In addition to the above two AMPs, Deslouches et al. designed a
infection. In relevant studies, the AMP P5 plays an antibacterial role by cyclopeptide leader peptide ZY4, which is stabilized by disulfide bonds.
destroying the biofilm and promotes the death of carbapenem-resistant It is a kind of AMP with high stability in vivo, which shows good activity
Pseudomonas aeruginosa (Martinez et al., 2019). The destruction of bio against standard strains and clinical MDR strains of Pseudomonas aeru
films opens up the possibility of antibiotic re-sensitization, and the use of ginosa and Acinetobacter baumannii (Mwangi et al., 2019). It has the
P5-like AMP in combination with antibiotics may be a promising advantages of high plasma stability and low drug resistance, and can
direction. penetrate the bacterial membrane to eliminate or even eradicate bac
teria. The authors found that administration of ZY4 in a mouse septi
6. Current advances in AMPs for the treatment of drug-resistant cemia infection model could reduce its susceptibility to Pseudomonas
bacterial infections aeruginosa pulmonary infection and inhibit the transmission of Pseudo
monas aeruginosa and Acinetobacter baumannii to target organs. The
The current advances in AMPs for the treatment of drug-resistant above results show that ZY4 is an ideal candidate drug against MDR
bacterial infections are classified into two categories: during the bacterial infection (Deslouches and Di, 2017). Similarly, the AMPR-11
research and development process, and already in use. from mitochondrial non-selective channel Romo1 also has
6
antibacterial activity against gram-positive and gram-negative bacteria during the clinical translation, the potential use of AMPs is limited
including many clinically isolated MDR strains (Lee et al., 2018). because of their innate drawbacks and complex drug-tissue situations.
Stated below are several most evident challenges of the development of
6.1.3. Resistance of the "ESKAPE" infections drug-resistant AMPs (Fig. 4).
"ESKAPE" comes from the first letters of several bacterial names:
Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Aci 7.1. Instability
netobacter baumannii, Pseudomonas aeruginosa and Enterobacter species,
also known as superbugs, which are a major group of highly drug- As peptide drugs, the stability of AMPs is of great concern while
resistant bacteria commonly seen in hospitals (Rice, 2008). many of them have a short half-life (Mahlapuu et al., 2020), which be
From a panel of synthetic AMPs, inspired by the structure of the comes an obstacle and limits their clinical application. As for topical
human cathelicidin, LL-37, the synthetic peptide SAAP-148 was selected application, bare AMPs are prone to destruction by the environment
as the most promising AMPs in reduction of bacterial counts (Scott et al., (hydrolysis, oxidation, photolysis) and wound related factors (alkaline
2002). It can kill bacteria more effectively than many known preclinical pH, proteolysis). As for systemic administration, rapid proteolytic
and clinical AMPs under in vitro physiological conditions. Anna et al. degradation in blood, enhanced hepatic and renal clearance (Vlieghe
found that SAAP-148 is very effective against ESKAPE pathogens and et al., 2010), and susceptibility to physiological salt concentrations
colistin-resistant Enterobacter cloacae, Escherichia coli and Klebsiella (Sarkar et al., 2021) attribute to their short half-life, ultimately limit the
pneumoniae. Their further experimental results showed that, compared efficient utilization of AMPs. Besides, poor penetration of the intestinal
with traditional antibiotics, SAAP-148 was active against mucosa reduces the possibility of oral administration for AMPs (Deptuła
antibiotic-sensitive strains in most cases and had 400-fold higher ac et al., 2018).
tivity against antibiotic-resistant strains (Anna, 2018). Because the sta
bility and bactericidal activity of the peptides were not affected by 7.2. Weak antibacterial activity
Hyproelose gel (Nes, 1997; Haisma et al., 2016), the authors used a
mouse model of chafing skin infection treated with Hyproelose ointment There’s always a trade-off between merits and demerits for AMPs,
containing SAAP-148 for 4 h. The results showed that it completely which is nothing else than the broad-spectrum antibacterial property
eradicates MRSA and MDR Acinetobacter baumannii biofilm-associated and the impressionable antibacterial activity simultaneously. Despite
infections in injured human and mouse skin. the fact that most AMPs show potent activity in vitro, the in vivo anti
Another common example is TC19, a synthetic peptide derived from bacterial activity can be weakened largely due to the complexity of
the human thromboxane 1-derived peptide L3 (Kwakman et al., 2011). microenvironment, such as the effects of proteases and changes in pH
Riool et al. carried out biophysical experiments on the interaction be values (Thapa et al., 2020). The net cationicity of cecropins, clavanins,
tween bacterial plasma membrane mimics and TC19. The results showed and protegrins is augmented by their C-terminal amidation. Obviously,
that the peptide had high selectivity to bacterial membrane and could the positive charge of them contributes to their interactions with anionic
effectively and quickly kill several MDR strains of ESKAPE in human microbial surface components such as lipopolysaccharide or various
plasma. The authors demonstrated that local application of Hyproelose anionic membrane phospholipids. As the pKa of histidine residue is
gel containing TC19 significantly reduced the number of MRSA and around 6.5, histidine-rich peptides like clavanin A have high net positive
MDR Acinetobacter baumannii in superficial infected wounds in mice. In charges at pH 5.5, while they are relatively uncharged at pH 7.4 (Lee
short, TC19 is a potential drug for the treatment of MDR skin wound et al., 1997). With the change in pH, the antibacterial activity of these
infections (Riool et al., 2020). AMPs could be affected, thus limiting their activity to the sites with a
neutral pH. Moreover, serum-susceptible AMPs such as LL-37, can bind
6.2. AMPs approved for clinical applications for drug-resistant bacteria to serum proteins and become inactive in human serum, thus reduce
antibacterial activity. When it comes to the AMPs that take effect against
6.2.1. polymyxin B superbugs, such as MRSA, their capacities for killing drug-resistant
AMPs have broad-spectrum bactericidal activity, and this property bacteria are shown to be limited or not effective-enough for clinical
makes them a promising therapeutic candidate, of which polymyxin B is improvement. For example, Omiganan, a synthetic indolicidin analogue
a good example. Produced by Bacillus polymyxa and introduced into AMP that has been investigated for treating moderate atopic dermatitis,
clinical practice successively in the 1950s (Zavascki et al., 2007), it failed to improve clinical symptoms in patients even though it showed
polymyxin B has rapid in vitro bactericidal activity against major the activity against Staphylococcus aureus and led to dysbiosis (Nie
drug-resistant gram-negative bacteria such as Pseudomonas aeruginosa, meyer-van der Kolk et al., 2022). Stated above show that AMPs are
Acinetobacter baumannii and Klebsiella pneumoniae, and is now used subject to the outer factors and environment, which leads to their weak
intravenously for the treatment of MDR infections caused by antibacterial activity in vivo and becomes a challenge facing the R&D of
gram-negative pathogens (Landman et al., 2008). AMPs.
6.2.2. Vancomycin 7.3. Toxicity

Vancomycin is a non-ribosomal synthetic tricyclic glycopeptide
consisting of a 7-membered tricyclic peptide structure attached to a Toxicity resulting from AMPs should be taken in consideration due to
vancomyl-glucose disaccharide, isolated in 1957 from Mycobacterium the direct influence on their application. Based on antibacterial mech
avium Orientalis. This antibiotic is one of the first discoveries in the field anism, AMPs with clear toxic effects can be classified into receptor-
and has been in clinical use for nearly 60 years (Laxminarayan, 2013). binding peptides and membrane-active peptides (Chen and Lu, 2020).
Vancomycin inhibits cell wall formation and thus is most effective Instead of killing the target bacteria directly, receptor-binding peptides
against gram-positive bacilli. It is used as a first-line agent in the treat exert bacteriostatic effect through modulating the immune system. With
ment of MRSA infections, including bacteremia, endocarditis, pneu the increase of AMPs’ concentration, off-target effects may arise and
monia, cellulitis, and osteomyelitis (Mermer et al., 2020). additional chronic inflammatory diseases such as atopic dermatitis, ro
sacea, psoriasis, and hidradenitis suppurativa could be triggered
7. Challenges of drug-resistant AMPs (Takahashi et al., 2018). Membrane-active peptides, for example,
pore-forming AMPs (alamethicin, melittin, etc.), have been verified to
With the increasing antibiotic-resistance, AMPs have attracted great have hemolytic and cytotoxic properties (Bechinger, 1997; Leitgeb et al.,
attentions due to their broad-spectrum antibacterial property. However, 2007, Raghuraman and Chattopadhyay, 2007) through interacting and
7
Fig. 4. Challenges of drug-resistant AMPs. 1.

AMPs are prone to wound related factors and
the microenvironment, such as hydrolysis,
oxidation and photolysis, which leads to their
short half-time. 2. The complexity of microen
vironment makes differences in effects on drug-
resistant bacteria, and results of clinical tests
always weaken in comparison with those in
vitro or in vivo. 3. The off-target effects raised by
AMPs may trigger additional chronic inflam
matory diseases, and show hemolytic and
cytotoxic properties. 4. The gene mutation,
which leads to resistance evolution, might
cause certain bacteria survive better in body. 5.
The long R&D cycle and high risks leads to low
investment return.
Table 1
Anti-MRSA AMPs.
AMP Name Sequence Activity Class Ref.
(Gþ/-)
Indolicidin ILPWKWPWWPWRR + /- IR13; Tet083; XXA, Trp-rich, bovine cathelicidin, cattle, ruminant, (Giacometti et al., 1998;
mammals; animals; BBN; BBPP/BBII; Derivatives: CP-11, MBI- Mataraci and Dosler,
549, Omiganan pentahydrochloride 2012)
SMAP-29 RGLRRLGRKIAHGVKKYGPTVLRIIRIAG + /- SMAP29, sheep myeloid AMP-29; SMAP-28, OaMAP28, ovine (Skerlavaj et al., 1999)
cathelicidin, sheep, ruminant, mammals, animals; BBomp; BBL;
derivatives: Ovispirin, OV-1, OV-2, OV-3, novispirin, novici
LL-37 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES + /- LL37; FALL-39; cathelicidin; UCLL1; human; chimpanzee; (Ciornei et al., 2005)
primates, mammals, animals; XXX; XXY; XXZ; BBBh2o, BBBm;
BBMm, BBPP, BBN, BBL, BBrsg, JJsn; Derivatives: many
BMAP-27 GRFKRFRKKFKKLFKKLSPVIPLLHLG + /- BMAP27, bovine myeloid antimicrobial peptide 27; bovine (Skerlavaj, et al. 1996)
cathelicidin, cattle, ruminant, mammals, animals; ZZHs; ZZP;
UCLL1; Derivatives: BMAP-18 and BMAP-15
BMAP-28 GGLRSLGRKILRAWKKYGPIIVPIIRIG + /- BMAP28, bovine myeloid antimicrobial peptide 28; bovine (Skerlavaj et al., 1996)
cathelicidin-5, cattle, ruminant, mammals, animals; BBMm;ZZP;
UCLL1; Derivatives: mBMAP-28
CPF-ST3 GLLGPLLKIAAKVGSNLL + /- XT-7; XXA, UCLL1c; frog, amphibians, animals, SeqAR (Subasinghage et al.,
2010)
Piscidin 1 FFHHIFRGIVHVGKTIHRLVTG + /- piscidin-1; Pis-1; fish, animals; Variants: Piscidin-1 N, piscidin- (Silphaduang and Noga,
1 H; ZZH; BBII, UCLL1 2001; Menousek et al.,
2012)
Chicken RFGRFLRKIRRFRPKVTITIQGSARFG + /- chicken cathelicidin 2; CMAP27, chicken myeloid antimicrobial (van Dijk et al., 2009)
CATH-2 peptide 27, Fowlicidin-2; chCATH-2; birds, animals; BBL;
Derivatives: F2,5,12 W
Brevinin- FLGSIVGALASALPSLISKIRN + /- XXA; UCLL1c; frog, amphibians, animals (Conlon et al., 2006)
1TSa
Brevinin- FLSLALAALPKFLCLVFKKC + /- Amurin-2c; frog, amphibians, animals; XXU; 1 S–
–S, UCSS1a; (Conlon et al., 2007;
1DYa Amurin-2a Zhang et al., 2018)
Brevinin- FLSLALAALPKLFCLIFKKC + /- Amurin-2; frog, amphibians, animals; XXU; 1 S–
–S, UCSS1a (Conlon et al., 2007;
1DYb Zhang et al., 2018)
Temporin- FLPLLASLFSRLF + XXA; UCLL1c; frog, amphibians, animals (Kim et al., 2001; Mishra
1Oc et al., 2018)
Temporin- SILPTIVSFLSKVF + XXA；UCLL1c; frog, amphibians, animals (Kim et al., 2000; Mishra
1Ga et al., 2018)
Temporin FLSIIAKVLGSLF + Temporin-1Vb, XXA, UCLL1c; frog, amphibians, animals (Conlon et al., 2005)
1Vb
Imcroporin FFSLLPSLIGGLVSAIK + scorpions, arachnids, Chelicerata, arthropods, invertebrates, (Zhao et al., 2009)
animals; XXA, UCLL1c
CPF-SE1 GFLGPLLKLGLKGVAKVIPHLIPSRQQ + /- frog, amphibians, animals; UCLL1 (Conlon et al., 2012)
CPF-SE2 GFLGPLLKLGLKGAAKLLPQLLPSRQQ + /- CPF-SP2; frog, amphibians, animals; UCLL1 (Conlon et al., 2012)
Temporin- FLPAALAGIGGILGKLF + /- frog, amphibians, animals; XXA; UCLL1c; BBMm (Abbassi et al., 2010)
SHd
Stigmurin FFSLIPSLVGGLISAFK + scorpions, arachnids, Chelicerata, arthropods, invertebrates, (de Melo et al., 2015)
animals; UCLL1a
MP-C LNLKALLAVAKKIL + /- mastoporan-C, insects, arthropods, invertebrates, animals. XXA; (Chen et al., 2018)
UCLL1c
Japonicin- FIVPSIFLLKKAFCIALKKC + /- frog, amphibians, animals; XXU; 1 S– –S, UCSS1a; BBMm (Yuan et al., 2019)
2LF
8
disassembling the membrane of eukaryotic cells, especially erythro hardly be seen on the list.
cytes, which leads to hemolysis (Maturana et al., 2017). The side-effects
of colistin include damage to the kidneys and central nervous system in 8. Latest methods and strategies on the development of AMPs
human body (Wolinsky and Hines, 1962; Poirel et al., 2017). against drug-resistant bacteria
With the rapid development and studies on AMPs, thousands of
AMPs that were synthesized or produced by living organisms have been In addition to traditional AMPs, there are new approaches and
recorded (Ageitos et al., 2017). To summarize the AMPs comprehen strategies available for the treatment of drug-resistant bacterial
sively and efficiently, we integrated the huge amounts of data from infections.
several AMP databases, such as APD3 (Wang et al., 2015) and CAMPR3
(Waghu et al., 2015). Among the 211 APD-recorded Anti-MRSA, 21 of 8.1. AMPs with nanotechnology
them are hemolytic peptides, which are listed in Table 1.
After comparing the MIC of six anti-MRSA with their hemolytic ac The use of nanoparticles (NPs) conjugated system for the delivery of
tivities, the multiples between the concentration at which 50% of red AMPs has recently gained attentions. NPs provide very large surface for
blood cells were lysed and MIC were comparatively small, reflecting in adsorption of AMPs and also prevent AMP self-aggregation (Sun et al.,
the cell selectivity value (CS value: HL50/MIC) of Ascaphin-8, DASamP1, 2018). Nanostructures have been identified as potential drug delivery
DASamP2, Lycotoxin I, Maculatin 1.3, Piscidin are 1, 15, 8, 12, 40, 4 and nanocarriers. As effective drug carriers, they should have two important
7 respectively (Menousek et al., 2012). In other studies, peptide XT-7 properties: no cytotoxicity and no immunogenicity. They can be inter
have shown strong activity against MRSA, gram-negative bacterium nalized into the cytoplasm without the use of any transfectants and
Escherichia coli and others (Ali et al., 2001), but it was also hemolytic transferred via endocytosis and exocytosis pathways independent of
with the CS value of 12. multi-drug efflux pumps. Nanotechnology-based therapies can enhance
the stability and efficacy of AMPs and reduce their toxicity to host tissue
7.4. Evolution of resistance against AMPs cells. The encapsulation of AMPs in nanomaterials has great potential
because of their small size, high surface area, and strong targeting
Research (Perron et al., 2006) has negated the earlier notion of capability (Lepeltier et al., 2020, Fadaka et al., 2021).
bacteria’s incapability of evolving resistance to AMPs, which means that Take the proline-rich AMP dimer A3-APO and its single chain
the use of AMPs also needs strict experiments to lower the risk of metabolite (APO monomer) as an example. The MDR Acinetobacter
evolutionary drug-resistant bacteria. In comparison with conventional baumannii strain, isolated from an injured soldier by researchers, was
antibiotics, due to the difference in pharmacodynamics, the inoculated into mice with burn wounds. A dose of 5 mg/kg A3-APO
dose-response curve of AMPs is steeper, indicating the low possibility of improves survival and reduces the bacterial counts in the blood and in
evolution of resistance against AMPs (Yu et al., 2016). However, there the wounds significantly better than any other antibiotic treatment
were reports on the resistance to certain AMPs. For example, Staphylo including colistin and imipenem. It not only improves the industrial
coccus aureus induced a specific protease, thus developing resistance to utility and commercial viability of the final product, but also provides
dermcidin. Some gram-negative bacteria also could modify their lipo added value in smart biomedical applications (Gera et al., 2022).
polysaccharide through a specific sensor (PhoP/PhoQ) system, which
resulted in decreased sensitivity to cationic AMPs (Lai et al., 2007). 8.2. AMPs combined with antibiotics
Moreover, the test in a model insect Tenebrio has shown that certain
AMP-resistant Staphylococcus aureus survived better in the host (El The combinations of antibiotics and AMPs are coming into the
Shazely et al., 2019), which is an evidence strengthening the early market. It is a potential therapeutic approach that can overcome anti
concern that potential cross-resistance to endogenous host AMPs might biotic resistance, improve bacteria-killing effect, and also reduce
arise by evolved resistance to therapeutically applied AMPs (Bell and toxicity and side effects. This strategy can lead to reducing side effects
Gouyon, 2003). At the same time, over 10 AMPs of human origin are and increasing the selectivity of compounds, while enhancing the
under clinical trials (Lazzaro et al., 2020), which might induce permeability of bacterial membranes and reducing the efflux of anti
cross-resistance to endogenous targets of the host. Exploiting AMPs from biotic drugs, thereby inhibiting bacterial survival (Harsh et al., 2017).
other plants and animals and choosing proper candidate for further For example, Li et al. demonstrated that the combination of the
studies are warranted. tetracycline antibiotic demeclocycline hydrochloride (DMCT) and the
AMP SAAP-148 had synergistic antimicrobial activity. It can be used
7.5. Economic issues on the studies of AMPs against MDR Pseudomonas aeruginosa PAO1 and Pseudomonas aeruginosa
ATCC27853 (Li et al., 2020). Furthermore, the combination of salicyl
Similar to most new drug research and development projects, a amine and colistin has been considered to be an effective strategy for
majority of researches and development of AMPs failed, because of killing MDR gram-negative bacteria, which can overcome the short
being not able to stand the lengthy time of experimental verifications or comings of poor membrane permeability of salicylamine (R et al., 2019).
clinical trials. Although antimicrobials against superbugs are becoming
increasingly important and urgent in this era and in the future, economic 8.3. Changing the structure of amino acid in AMPs
issues hanging over AMPs’ research and development, resulting from the
high R&D investment needed and the extremely low conversion rate, are There are many obstacles of using AMPs in clinical application, such
challenges that cannot be ignored. as toxicity, instability and high cost. To solve these problems, many
On the other hand, once drug resistance developed, all the efforts on methods have been reported. For instance, substitution Trp and Phe
new antibiotics or AMPs’ development were wasted, which results in the residues with less hydrophobic amino acids can decreases the toxicity of
survival of R&D can only occur in big pharma such as Novartis, Astra AMPs. Introduction of non-natural amino acids (mainly D-form amino
Zeneca, Sanofi and Allergan (Hamad et al., 2019). acids), cyclization or modification of the terminal regions of amino acids
Using a cross-sectional comparison, we can see that the return-on- by acetylation or amidation can improve the stability of peptides (Zhang
investment potential in the anti-infection field is dwarfed by that in et al., 2011).
other therapeutic areas (Payne et al., 2015). Besides, the effect of AMPs One effective method used to enhance the proteolytic resistance and
decides their short duration of treatment, which is always below ten antimicrobial activity of peptides involves the addition of unnatural
days. Nowadays, among the top-50 list of pharmaceutical products amino acids. In one study, L-ornithine was used to design star-shaped
referenced by worldwide sales, AMPs, even anti-infection drugs, could poly-L-ornithine peptides against Pseudomonas aeruginosa. In vitro and
9
in vivo studies showed that this peptide has potent antimicrobial and Ciornei, C.D., et al., 2005. Antimicrobial and chemoattractant activity,
lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs
anti-biofilm activities and has great wound healing properties against
of human cathelicidin LL-37. Antimicrob. Agents Chemother. 49 (7), 2845–2850.
pathogens in mouse models of infection (Thakur et al., 2022). https://doi.org/10.1128/AAC.49.7.2845-2850.2005.
A previous study showed that a peptidoglycan residue ends up with Conlon, J.M., et al., 2005. Purification and characterization of antimicrobial peptides
‘D-alanyl-D-lactate’ in vancomycin-sensitive bacteria and ‘D-alanyl D- from the skin secretions of the carpenter frog Rana virgatipes (Ranidae, Aquarana).
Regul. Pept. 131 (1–3), 38–45. https://doi.org/10.1016/j.regpep.2005.06.003.
lactate/D-alanyl D-serine’ in vancomycin-resistant bacteria (Sharma, Conlon, J.M., et al., 2006. Antimicrobial peptides from the skin of the Tsushima brown
2021). This suggests that changing amino acid configuration may play a frog Rana tsushimensis. Comp. Biochem Physiol. C. Toxicol. Pharm. 143 (1), 42–49.
significant role in drug-resistant AMPs. https://doi.org/10.1016/j.cbpc.2005.11.022.
Conlon, J.M., et al., 2007. Cytolytic peptides belonging to the brevinin-1 and brevinin-2
families isolated from the skin of the Japanese brown frog, Rana dybowskii. Toxicon
9. Conclusions 50 (6), 746–756. https://doi.org/10.1016/j.toxicon.2007.06.023.
Conlon, J.M., et al., 2012. Host-defense peptides in skin secretions of the tetraploid frog
Silurana epitropicalis with potent activity against methicillin-resistant
In conclusion, this review discusses the mechanisms of drug resis Staphylococcus aureus (MRSA. Peptides 37 (1), 113–119. https://doi.org/10.1016/j.
tance, and provides ideas for the application of AMPs in drug-resistant peptides.2012.07.005.
bacteria. The broad-spectrum antibacterial activity and the strong ef Coorens, M., et al., 2017. Interspecies cathelicidin comparison reveals divergence in
antimicrobial activity, TLR modulation, chemokine induction and regulation of
fect on gram-negative bacteria of AMPs make them promising antimi phagocytosis. Sci. Rep. 7 (1), 40874. https://doi.org/10.1038/srep40874.
crobial agents. Inevitably, AMPs have disadvantages like poor stability, de Melo, E.T., et al., 2015. Structural characterization of a novel peptide with
weak antibacterial activity, and economic issues, which need to be antimicrobial activity from the venom gland of the scorpion Tityus stigmurus:
Stigmurin. Peptides 68, 3–10. https://doi.org/10.1016/j.peptides.2015.03.003.
overcome to make AMPs the mainstream drug for development. Hope Deptuła, M., et al., 2018. Antibacterial peptides in dermatology–strategies for evaluation
fully, the increasing development of AMPs could make the process of of allergic potential. Molecules 23 (2), 414. https://doi.org/10.3390/
overcoming drug resistance safer and more effective, ultimately molecules23020414.
Deshayes, C., et al., 2021. Drug delivery systems for the oral administration of
achieving the goal of eradicating drug-resistant bacteria.
antimicrobial peptides: promising tools to treat infectious diseases. Front Med
Technol. 3, 778645 https://doi.org/10.3389/fmedt.2021.778645.
Ethical Approval Deslouches, B., Di, Y.P., 2017. Antimicrobial peptides: a potential therapeutic option for
surgical site infections. Clin. Surg. 2, 1740 https://pubmed.ncbi.nlm.nih.gov/
30135956/.
Not applicable. Diene, S.M., et al., 2011. Real-time PCR assay allows detection of the New Delhi metallo-
β-lactamase (NDM-1)-encoding gene in France. Int. J. Antimicrob. Agents 37 (6),
544–546. https://doi.org/10.1016/j.ijantimicag.2011.02.006.
Competing Interests Du, D., et al., 2018. Multidrug efflux pumps: structure, function and regulation. Nat. Rev.
Microbiol. 16 (9), 523–539. https://doi.org/10.1038/s41579-018-0048-6.
El Shazely, B., et al., 2019. In vivo exposure of insect AMP resistant Staphylococcus
Authors declare that they have no conflict of interest. aureus to an insect immune system. Insect Biochem Mol. Biol. 110, 60–68. https://
doi.org/10.1016/j.ibmb.2019.04.017.
Acknowledgements Elsalem, L., et al., 2022. WLBU2 antimicrobial peptide as a potential therapeutic for
treatment of resistant bacterial. Turk. J. Pharm. Sci. 19 (1), 110–116. https://doi.
org/10.4274/tjps.galenos.2020.43078.
This work was supported by the National Natural Science Foundation Erica, S.L., C, J.A., et al., 2006. Cyclic MrIA: a stable and potent cyclic conotoxin with a
of China (No. 31900984), the Chongqing Natural Science Foundation novel topological fold that targets the norepinephrine transporter. Am. Chem. Soc.
49, 6561–6568. https://doi.org/10.1021/jm060299h.
(No. CSTB2022NSCQ-MSX0575), the Fundamental Research Funds for Fadaka, A.O., et al., 2021. Nanotechnology-based delivery systems for antimicrobial
the Central Universities (No. D5000210899), and National Undergrad peptides. Pharmaceutics 13 (11), 1795. https://doi.org/10.3390/
uate Training Programs for Innovation and Entrepreneurship (Nos. pharmaceutics13111795.
Fca, B., et al., 2019. Biopolymeric pellets of polyvinyl alcohol and alginate for the
XN2022273 and S202210699342).
encapsulation of Ib-M6 peptide and its antimicrobial activity against E.coli. Heliyon
5 (6), e01872. https://doi.org/10.1016/j.heliyon.2019.e01872.
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Drug Resistance Updates 68 (2023) 100954

Contents lists available at ScienceDirect

Drug Resistance Updates

Antimicrobial peptides for combating drug-resistant bacterial infections

1. Introduction used in combination with emerging technologies (Wu et al., 2018). As

2. Generation of drug resistance in bacteria 2.1.2. Extended spectrum β-lactamases (ESBLs)

Fig. 1. Schematic diagram of AMPs in

Fig. 2. Schematic representation of the mechanisms of

Fig. 3. Overview of the mechanism of AMPs in

6.2.2. Vancomycin 7.3. Toxicity

Fig. 4. Challenges of drug-resistant AMPs. 1.

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