Open access peer-reviewed chapter

Peptides with Therapeutic Potential against Acinetobacter baumanii Infections

Written By

Karyne Rangel and Salvatore Giovanni De-Simone

Submitted: 23 July 2021 Reviewed: 09 September 2021 Published: 16 April 2022

DOI: 10.5772/intechopen.100389

From the Edited Volume

Insights on Antimicrobial Peptides

Edited by Shymaa Enany, Jorge Masso-Silva and Anna Savitskaya

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Antibiotic poly-resistance (multi drug-, extreme-, and pan-drug resistance) is a major global threat to public health. Unfortunately, in 2017, the World Health Organization (WHO) introduced the carbapenemresistant isolates in the priority pathogens list for which new effective antibiotics or new ways of treating the infections caused by them are urgently needed. Acinetobacter baumannii is one of the most critical ESKAPE pathogens for which the treatment of resistant isolates have caused severe problems; its clinically significant features include resistance to UV light, drying, disinfectants, and antibiotics. Among the various suggested options, one of the antimicrobial agents with high potential to produce new anti-Acinetobacter drugs is the antimicrobial peptides (AMPs). AMPs are naturally produced by living organisms and protect the host against pathogens as a part of innate immunity. The main mechanisms action of AMPs are the ability to cause cell membrane and cell wall damage, the inhibition of protein synthesis, nucleic acids, and the induction of apoptosis and necrosis. AMPs would be likely among the main anti-A. baumannii drugs in the post-antibiotic era. Also, the application of computer science to increase anti-A. baumannii activity and reduce toxicity is also being developed.


  • RAMP
  • Acinetobacter baumannii
  • resistance
  • action mechanism

1. Introduction

Microbial infections contribute substantially to global mortality trends. Antibiotic resistance is one of the biggest challenges for the clinical sector, industry, environment, and societal development. Unfortunately, the emergence of drug-resistant pathogens is rapidly growing, and the world is heading toward the post-antibiotic era [1, 2]. Bacteria possess three defined types of antimicrobial resistance: intrinsic, acquired, and phenotypic or adaptive resistance [3, 4, 5, 6, 7, 8, 9, 10, 11]. Although there are multiple causes of the resistance phenomenon, it is considered that antimicrobial resistance is an old natural phenomenon when microbes are exposed to antimicrobial drugs, with an accelerated evolution triggered not only by the abusive use of antibiotics but also such as wrong choices, inadequate dosing, and poor adherence to treatment guidelines that contribute to the increasing antimicrobial resistance selection [12, 13]. In addition, antibiotic treatment for difficult-to-treat multidrug-resistant bacterial infections is limited [13]. ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, Enterobacter species) are among the most common opportunistic pathogens in nosocomial infections [14]. The abbreviation ESKAPE reflects the ability of these organisms to “escape” killing by antibiotics and defy eradication by conventional therapies, which accounts for increased morbidity and mortality for improved resource utilization in healthcare [15]. One of the ESKCAPE pathogens responsible for nosocomial and community-acquired infections is A. baumannii, a Gram-negative, non-motile, non-fermentative, and non-sporulated bacterium Moraxellaceae family [16] that is part of the Acinetobacter calcoaceticusA. baumannii complex (Acb). Currently, six species, namely A. calcoaceticus, A. baumannii, A. pittii, A. nosocomialis, A. seifertii, and A. lactucae (a later heterotypic synonym of A. dijkshoorniae) [17, 18], belonging to the Acb complex have been associated with human diseases [19]. Even though these species differ in antimicrobial resistance, pathogenicity, and epidemiology [20], the Acb complex is genetically and physiologically highly related, making it difficult to distinguish them phenotypically with standard laboratory methods [21]. Of all the species in the Acb complex, A. baumannii is the most widespread in hospitals, even associated with an increased risk of morbidity, mortality, high treatment costs, and long periods of hospitalization [22]. A. baumannii causes various infections, including wounds, skin, urinary tract infections, pneumonia, meningitis, and bacteremia [23, 24]. There are several nomenclatures in the literature based on the number of resistance classes of antibiotics. According to Magiorakos et al. (2012), a multidrug-resistant (MDR) strain is resistant to at least one antimicrobial in more than three classes of antimicrobials; and extensively drug-resistant (XDR) strain is one resistant to at least one antimicrobial in all classes of antimicrobials except two or fewer types, and a pan drug-resistant (PDR) strain is resistant to all antimicrobial agents [25]. A. baumannii has globally emerged as a highly troublesome nosocomial pathogen revealing MDR, XDR, and PDR phenotypes, and unfortunately, evidence has shown an increased A. baumannii antibiotic resistance over time [26]. A. baumannii is one of the most critical and fearful pathogens with treatment options limited due to many aspects: its extended virolome and resistome, evasion of the host’s immune effectors, ability to survive in extreme environmental conditions, to grow in biofilms, and to switch to latent growth forms with a minimal metabolic rate [27, 28]. The World Health Organization (WHO) has recently published a report, which also highlighted A. baumannii resistant to carbapenems (CRAb) [29, 30] which was classified in the group of “priority 1 for research and develop new antibiotic treatments” and was considered as a “critical” pathogen [31]. One of the antimicrobial agents with high potential for research and development of anti-Acinetobacter drugs is the antimicrobial peptides [32]. This chapter aimed to review the powerful antimicrobial peptides described with activity against A. baumannii multiresistant.


2. Antimicrobial peptides

Antimicrobial peptides (AMPs) may represent an alternative to current antibiotics in MDR A. baumannii ESKAPE pathogen [33]. AMPs (also known as host defense peptides) are small polycationic peptides naturally produced by living organisms with both microbicidal and immunomodulatory activities, acting as a primary barrier against pathogens, including protozoa, víruses, bacteria, archaea, fungi, plants, and animals as a part of innate immunity system [34, 35, 36, 37, 38, 39, 40, 41]. However, the computational design of synthetic AMPs with improved activity is also being developed [42]. They interact with cell membrane through electrostatic interactions, causing the inhibition of protein and nucleic acid synthesis and final cellular lysis by apoptosis and necrosis [43, 44]. In addition to the antimicrobial properties, some AMPs have other activities, such as anticancer antioxidant, wound healing, immunoregulatory [38, 45, 46]. AMPs also play an essential role in regulating immune processes such as activating and recruiting immune system cells, angiogenesis, and inflammation [47]. AMPs are amphipathic molecules with a positive electric charge, varying molecular weight, and containing about 11–50 amino acid residues [47, 48]. AMPs are classified into α-helical, β-sheet, and extended peptide families [49, 50, 51] and interact with the membranes initially through electrostatic and hydrophobic interactions (Figure 1), accumulating at the surface and self-assemble on the bacterial membrane after reaching a particular concentration [52, 53].

Figure 1.

Interaction of cationic AMPs with eukaryotic and bacterial membranes. Images were created using

At this stage, various models have been proposed to describe the action of AMPs. The models can be classified under two broad categories: transmembrane pore (TMP) and non-pore models (NPM), and the TMP can be further subdivided into the barrel-stave pore and toroidal pore models. In the barrel-stave model, the AMPs are initially oriented parallel to the membrane but eventually insert perpendicularly in the lipid bilayer [54] (Figure 2A), thus promoting lateral peptide-peptide interactions, like that of membrane protein ion channels. Peptide amphipathic structure (α and/or β sheet) is essential in this pore formation mechanism as the hydrophobic regions interact with the membrane lipids and hydrophilic residues from the lumen of the channels [55, 56]. A unique property associated with AMPs in this category is a minimum length of ∼22 residues (α helical) or ∼ 8 residues (β sheet) to span the lipid bilayer. Only a few AMPs, such as alamethicin [57], pardaxin [58, 59], and protegrins [55], have been shown to form barrel stave channels.

Figure 2.

Mechanisms of action of AMPs in bacteria. A) Barrel-stave model: AMPs stack into the bilayer of the cell membrane to form a channel. (B) Toroidal pore model: Accumulation of vertically and bend embedded AMPs in the cell membrane to form a pore structure, (C) carpet model: Distribution of AMPs on membrane surface that evolve to detergent-like mode, forming micelles, (D) images were created using

Furthermore, in the toroidal pore model, the peptides also insert perpendicularly in the lipid bilayer, but specific peptide-peptide interactions are not present [57]. Instead, the peptides induce a local curvature of the lipid bilayer with the pores partly formed by peptides and partly by the phospholipid head group (Figure 2B). Thus, the dynamic and transient lipid-peptide supramolecule is known as the “toroidal pore.” The distinguishing feature of this model compared to the barrel-stave pore is the net arrangement of the bilayer. In the barrel-stave pore, the hydrophobic and hydrophilic sequence of the lipids is maintained, whereas, in toroidal pores, the hydrophobic and hydrophilic arrangement of the bilayer is disrupted, thus providing alternate surfaces for the lipid tail and the lipid head group to interact with. Furthermore, as the pores are transient upon disintegration, some peptides translocate to the inner cytoplasmic leaflet entering the cytoplasm and potentially targeting intracellular components [60]. Other features of the toroidal pore include ion selectivity and discrete size [61]. Several AMPs such as magainin 2 [62], lacticin Q [62], aurein 2.2 [63], and melittin [57, 62] have been shown to form toroidal pores. In addition, the type of pore started by aurein 2.2 has been shown to depend on the lipid composition: In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycerol-3-phospho-(1′-rac-glycerol) POPG (1:1) membrane model, the peptides induce toroidal pores, whereas in a 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) DMPG (1,1) membrane model, the peptides work in a detergent-like model (details below) indicating the importance of the hydrophobic thickness of the lipid bilayer and the membrane composition [64, 65]. Ultimately, both pore-forming models (toroidal pore and barrel) lead to membrane depolarization and eventually cell death.

AMPs can also act without forming specific pores in the membrane. One of these models is designated as the carpet model [61, 62, 66]. In this case, the AMPs adsorb parallel to the lipid bilayer and reach a threshold concentration to cover the surface of the membrane, thereby forming a “carpet” (Figure 2C) and leading to unfavorable interactions on the membrane surface. Consequently, the membrane integrity is lost, producing a detergent-like effect, which eventually disintegrates the membrane by forming micelles. The final collapse of the membrane bilayer structure into micelles is the detergent-like model (Figure 2D). The carpet model does not require specific peptide-peptide interactions of the membrane-bound peptide monomers; it also does not require the peptide to insert into the hydrophobic core to form transmembrane channels or specific peptide structures [67]. Many peptides act as antimicrobial agents despite their specific amino acid composition or the length of the sequence. Such AMPs typically act using the carpet model [66] at high concentrations because of their amphiphilic nature. Examples of AMPs acting by the carpet model are cecropin [68], indolicidin [69], aurein 1.2 [67], and LL-37 [66].

Overall, there are many models to describe the MOA of AMPs. In addition to those given above, other related models include the interfacial activity model, the electroporation model, and the Shai-Huang-Matsazuki model [62]. Some models do not make the specific distinctions shown in Figure 2. For example, it has been suggested that the carpet-like mechanism is a prerequisite step for the toroidal pore model [62]. Most studies to elucidate the MOA of AMPs involve the use of model membranes. The mode of action of only a few AMPs has been investigated with whole bacterial cells using imaging techniques [70, 71]. Different results may be obtained using other membrane models or assay conditions; for example, more than one MOA is possible for certain AMPs such as BP100 as the peptide-to-lipid ratio changes [72], indicating that the models described here may or may not translate directly to what is occurring in bacteria.

An online antimicrobial peptide database, APD3, list examples of AMPs, including both synthetically synthesized and compounds produced by living organisms [37]. In addition, many AMPs are currently being studied to elucidate their therapeutic efficacy against A. baumannii strains (Table 1).

PeptideRef.SequenceStructureMIC against A. baumannii (μg/mL)Source
KS-12KRIVQRIKDFLR (12aa)AH25664–256
CATH-BF derivative (Cath-A and OH-[54]KFFRKLKKSVKKRAKEFFKKPRVI GVSIPF(30aa)AH8–32Bungarus fasciatus (Snake venom)
ZY4 cathelicidin-BF-15 derived[55]VCKRWKKWKR KWKKWCV-NH2 (17aa)Cyclic SH-bridge4.6–9.4
OH-CATH30[57]KFFKKLKNSVKKRAKKFFKKPRVI GVSIPF(30aa)AH1010King cobra (Snake venon)
DOH-CATH30(KFFKKLKNSVKKRAKKFFKKPRVI GVSIPF, italics indicate D-amino acids)AH1.56–12.5
D-Myrtoxin-Mp 1a (Mp1a)[58]IDWKKVDWKKVSKKTCKVMXKA CKEL-NH2 (26aa-aipha chain)
LIGLVSKGTCVLXKTVCKKVLKQNH2 (23aa-beta chain)Helical heterodim25 nMMyrmecia pilosula
Venon cocktail proteins[59]Cocktail50.6% of inhibition at 20 mg/mL of venomLeiurus quinquestriatus (Scorpion venom)
Ranalexin[60]LGGLIKIVPAMICAVTKKC (19aa)AH4–18Rana catesbeiana (American bulfrog)
Mini-ChBac7.5 Nα[62]RRLRPRRPRLPRPRPRPRPRPR (22aa)AH2 μMDomestic goat (Capra hircus)
WAM-1[63, 64]KRGFGKKLRKRLKKFRNSIK KRLKNFNVVIPIPLPG (36aa)AH8.124–64Tammar wallaby (Macropus eugenii)
Indolicidin[65, 66, 68]LPWKWPWWPWRR-NH(2) (13aa)Other structure42–64Cytoplasmic granules of the bovine neutrophils
Bactenecin[65, 67, 69]LCRIVVIRVCR (12aa)B-turn structure Ciclyc64Bovine neutrophil granules, Caprine
HNP-1[65]ACYCRIPACIAGERRYGTCIYQGRL WAFCC (30aa)AH50H. sapiens (Polymorphonuclear neutrophil)
CL defensin[74]ATCDLFSFQSKWVTPNHAACAAH CTARGNRGGRCKKAVCHCRK (43aa)AH, antiparallel B-sheet; N-terminal loopCimex Lectularius (Bedbug)
HBD-2[75]GIGDPVTCLKSGAICHPVFCPRRY KQIGTCGLPGTKCCKKP (41aa)Beta3.90–9.353.25–4.5Epithelial lining of respiratory /urinary tracts
Magainin-1[65, 77]GIGKFLHSAGKFGKAFVGEIMKS (23aa)AH256Frog skin peptide
Magainin-2[65, 77, 78]GIGKFLHSAKKFGKAFVGEIMNS (23aa)AH9.8–644.9–64
Pexiganan[79, 80, 81]GIGKFLKKAKKFGKAFVKILKK (22aa)AH1–81–8Frog skin peptide
Aurein 1,2[81]GLFDIIKKIAESF (13aa)AH16Frog skin peptide
Citropin 1.1.GLFDVIKKVASVIGGL-NH2 (16aa)AH16
OmigananILRWPWWPWRRK-NH2 (12aa)AH32
r-OmigananKRRWPWWPWRLI-NH2 (12aa)AH16
Temporin AFLPLIGRVLSGIL-NH2 (13aa)AH128
Brevinina 2 (B2RP)[82]GIWDTIKSMGKVFAGKILQNL-NH(2) (21aa)AH297–13.9Frog skin peptide
[D4K] B2RP[83, 84]GIWKTIKSMGKVFAGKILQNL⋅NH 2 (21aa)AH4–164–16Frog skin peptide
B2RP-Era[83, 85]GVIKSVLKGVAKTVALGML⋅NH2 (19aa)AH8–328–64Frog skin peptide
Alytesirin-1c[86]GLKEIFKAGLGSLVKGIAAHVASNH2 (23aa)AH11.3–22.6Frog skin peptide
[E4k] Alytesirin-1c[83, 84]GLKEIFKAGLGSLVKGIAAHVAS⋅NH2 (23aa)AH4–164–16Frog skin peptide
[S7K, G11K] Alytesirrin-2a[87]ILGKLLKTAAKLLSNL.NH2 (16aa)AH8Frog skin peptide
PGLa-AM1[83, 88]GMASKAGSVLGKVAKVALKAAL⋅NH2 (22aa)AH16–12816–128Frog skin peptide
CPF-AM1[83, 89, 90]GLGSVLGKALKIGANLL(19aa)AH16–1284–128Frog skin peptide
CPF-B1[91]GLGSLLGKAFKIGLKTVGKMMG GAPREQ (28aa)11.4–22.8Frog skin peptide
CPF-C1[90]GFGSLLGKALRLGANVL 917aa)5Frog skin peptide
[E6k,D9k] Hymenochirin-1B[92]LKLSPKTKDTLKKVLKGAIKGAIA IASMA-NH2 (29aa)AH4.9Frog skin peptide
Hymenochirin-1 Pa[93]Frog skin peptide
[G4K] XT7[83, 94]GLLGPLLKIAAKVGSNLL.NH2 (18aa)AH4–324–64Frog skin peptide
Buforin II[66, 77, 95, 96]TRSSRAGLQFPVGRVHRLLRK (21aa)AH8–19.50.25–39Frog skin peptide
Melittin[65, 97, 98]GIGAVLKVLTTGLPALISWIKRKR QQ (26aa)AH0.25–40.25–25European honeybee (Apis mellifera)
Cecropin A[65, 99]KWKLFKKIEKVGQNIRDGIIKAGP AVAVVGQATQIAK (37aa)AH320.5–32Cecropia moth (Hyalophora cecropia)
BR003-cecropin A[100]GGLKKLGKKLEGAGKRVFNAAEK ALPVVAGAKALRK (36aa)55Aedes aegypti
Cecropin P1[65, 102]SWLSKTAKKLENSAKKRISEGIAIA IQGGPR (31aa)1.6Pig (Ascaris suum)
Myxinidin 2[104]KIKWILKYWKWS (12aa)AH12.5Myxine glutinosa L
Myxinidin 3RIRWILRYWRWS (12aa)B-sheet6.3
FLIP 7[105]???Calliphora vicina (Medicinal Maggots)
Mastoparan[65, 106, 107]INLKALAALAKKIL (14aa)AH4Vespula lewisii (Hornet venom)
Mastoparan-AF (EMP-AF)[108]INLKAIAALAKKLF-NH2 (14aa)AH2–162–16Hornet venom (Vespa affinis)
Histatin-8[65]KFHEKHHSHRGY (12aa)AH8H. sapiens
Tachyplesin III[84]KWCFRVCYRGICYRKCR-NH2 (17aa)B-sheet 2 dissulfite bridgesHorseshoe crabs (Tachypleus gigas) and (Carcinoscorpius rotundicauda)
RR[111, 112]WLRRIKAWLRR (11aa)AH25–99Computationally designed
RR-4[112]WLRRIKAWLRRIKA (14aa)Ah3–6
DP7[113, 114, 115]AH4–16
Omega 76-shuft1[116]AFLLKKKKGIIFFEKAKKGKAH4–16
′Ω17 family peptides[116]RKKAIKLVKKLVKKLKKALK(20aa)AH21–8
′Ω76 family peptides[116]FLKAIKKFGKEFKKIGAKLK (20aa)AH42–8
Stapled AMP Mag (i + 4)1, 15(A9 K, B21A, N22 K, S23 K)[117]Mag(i + 4)1,15(A9K,B21A,N22K,S23K)complexNA, based in magainin 2 structure
PNA (RXR)4 XB[118]Peptide nucleic acid conjugated to (RXR)4 Phosphorodiamidate Morpholino Oligomers
HP(2–9)-ME(1–12) (HPME)[119]AKKVFKRLGIGAVLKVLTTG (20aa)AH6.253.12–12.5Chimeric peptide
HP(2–9)-MA(1–12) (HPMA)AKKVFKRLGIGKFLHSAKKF-NH2 (20aa)AH6.253.12–6.25Chimeric peptide
CA(1–8)-ME(1–12) (CAME)KWKLFKKIGIGAVLKVLTTG-NH2 (20aa)Ah3.123.12–12.5Chimeric peptide
CA(1–8)-MA(1–12) (CAMA)KWKLFKKIGIGKFLHSAKKF-NH2 (20aa)AH12.53.12–12.5Chimeric peptide
Hp l404 analogs (A, K, V, L, I, W)[120, 121]GILGKLWEGVKSIF-NH2 (14aa)AH3.13–12.53.13–16.25Venom gland scorpion (Heterometnus pertersii)
Octominin[122]GWLIRGAIHAGKAIHGLIHRRRH (23aa)AH5Synthetic derived, defensin 3 of Octopus minor
Ceragenins; CSA-192; CSA-131; D-150-177C; HBcARDderivative[123]Steroids compounds???Cholic acid synthetic mimics,
Protegrin-1[124]RGGRLCYCRRRFCVCVGR-NH2(18aa)AHCimex lectularius
Nuripep 1653[126]VRGLAPKKSLWPFGGPFKSPFN (22aa)AH12Derived from the P54 nutrient reservoir protein (aa 271–292) pea protein from Pisum sativum
Agelaia-MPI[127]INWLKLGKAIIDAL (14aa)AH6.2512.5–25Agelaia pallipes pallipes
Polybia-MPII[127]INWLKLGKMVIDAL (14aa)AH12.525Pseudopolybia vespiceps testacea
Polydin-I[127]AVAGEKLWLLPHLLKMLLTPTP (22aa)AH>25>25Polybia dimorpha (Social wasp)
Con10[127]FWSFLVKAASKILPSLIGGGDDNK SSS (27aa)AH12.512.5Scorpion venoms (Opisthacanthus cayaporum)
Delfibactin A[128]C40H68N14O1816Gram-negative bactéria Delfia spp.
WLBU2- arginine-rich amphiphilic peptide[129]RRWVRRVRRWVRRVVRVVRRWV RR (24aa)∼7.484∼7.484Skin wounds
α-Helical-26 (A12L/A20L)[130]Ac-KWKSFLKTFKSLKKTVLHTLLK AISS-NH2AH0.5–1.0D- and L-diastereomeric peptides
Cy02 (cyclotide)[131]????????????Viola odorata
Bicarinalin (YRTX-Tb1a)[132]KiKIPWGKVKDFLVGGMKAV (20aa)AH4Tetramorium bicarinatum venom
Glatiramer acetate (synthetic COP-1)[132]syntheticReduct viable cellsReduct viable cellsHomo sapiens
Lactoperoxidase (Lpo)[133]Large proteincomplexInhibition effects, significant clearance of A. baumannii in lung and blood cultureCamel (Colostrum milk)
Lactoferrin (Lf)Large proteincomplex
Artlysin Art-175[134]Comprises a modified variant of endolysin KZ144 with an N-terminal fusion to SMAP-294–20Pseudomonas aeruginosa bacteriophage
Epsilon-poly L-lysine (EPL)-catechol[135]Complex???Reducing bacterial burden in vivoStreptomyces albulus derived
Chex1-Arg20 amide (ARV-1502)[136]H-Chex-Arg-Pro-Asp-Lys-Pro-Arg-Pro-Tyr-Leu-Pro-Arg-Pro-Arg-Pro-Pro-ArgPro-Val-Arg-NH2???Reduction of bacterial loadNA
I16K-piscidin-1 and analogs[137]FFHHIFRGIVHVGKTIHRLVTG (22aa)???3.1Hybrid striped bass Morone saxatilis x M. chrysops
Nodule-specific cysteine-rich (NCR) peptide and its derivatives[138]RNGCIVDPRCPYQQCRRPLYCRRR (24aa)AH1.6–25 MBCMedicago trunculata
TAT-RasGAP317–326 anticancer peptide[139]G48RKKRRQRRR57 + W317MWVTNLRTD326AHGrowth inhibitory effectChimeric (cell penetrating sequence + Src homology sequence)
D-150-177C, HBcARD derivative peptide[140]RRRGRSPRRRTPSPRRRRSQSPRR RRSC (28AA)AH1616–32Hepatitis B virus
Colistin (Polymyxin E)[141]C52H98N16O13 (cyclic compound)Antibiofilm, side effectsBacillus colistinus
PlyF307 (P307)[142]146 aa (Access number KJ740396)?750750–2000Phage Lysin
N10[143]ACKDVNTSMCGGK (13aa)AH500500Blood biopanning
NB2ACERSIRTVCGGK (13aa)AH500500Biofilm biopanning
Melittin with imipenem (IPM)[144]GIGAVLKVLTTGLPALISWIKRKR QQ (26aa) + IPMAH0.31–0.370.12–0.25European honeybee and antimicrobial
Melittin with colistin (COL)GIGAVLKVLTTGLPALISWIKRKR QQ (26aa) + COLAH0.37–0.50.19–0.37

Table 1.

List of AMP with activity anti-A. baumannii.

NA, not available; AH, alpha helical; IPM, imipenem; COL, colistin.

2.1 Cathelicidins

Cathelicidins are a group of cationic AMPs (CAMPs) (with more than 30 members) detected in the immune system of some vertebrates that have in their structure two domains involved in antimicrobial activity [145]. Compared with carbapenems (imipenem and meropenem), which are considered the drugs of choice for infections caused by MDR A. baumannii (MIC = 16–32 mg/L) [146], these peptides exhibit excellent activity.

2.1.1 LL-37

The most studied member of the cathelicidins family is LL-37 (Human cathelicidin) with an α-helical structure. It is produced by many cell types as a part of innate immunity and exhibits broad-spectrum microbicidal activities against Gram-positive and Gram-negative bacteria by plasma-membrane disruption [147]. Other properties were also described, like immunomodulation properties such as chemoattraction and activation of various immune cells, neutralizing the lipopolysaccharide (LPS), regulating the inflammatory response, wound closure, and chemotaxis [38, 148, 149, 150, 151]. Feng et al. Investigated the anti-A. baumannii activity of LL-37 and fragments KS-30 and KR-12 against one sensitive and four MDR A. baumannii clinical isolates [73]. The minimum inhibitory concentration (MIC) for three pieces of KS-30, KR-20, and KR-12 was 8–16, 16–64, and 128–256 μg/ml, respectively. At the same time, LL-37 inhibited all sensitive and drug-resistant strains at the concentration of 16–32 μg/ml. Furthermore, LL-37 and the fragment KS-30 have been found to significantly inhibited and dispersed the A. baumannii biofilm in abiotic surfaces at 32 and 64 μg/ml, respectively [73]. A panel of synthetic peptides based on human LL-37 AMP shows potent microbicidal activity against several ESKAPE pathogens without selecting resistance and can also eliminate persister cells and biofilms of P. aeruginosa, A. baumannii, and S. aureus in the micromolar scale [74]. SAAP-148 is an α-helical AMP, able to suppress MDR A. baumannii without causing resistance and prevents biofilm formation. Studies showed that this peptide could inhibit the growth of A. baumannii MDR at a concentration of 6 μg/m. Treatment with this peptide (animal model) appointment has been shown to eliminate acute and biofilm-related infections by A. baumannii in an ex vivo human skin infection model and an in vivo murine skin infection model at concentrations above 5% [74].

2.1.2 Snake cathelicidins

The anti-A. baumannii activity among the cathelicidins isolated from snakes has been reported for the peptides cathelicidin-BF (Cath-BF) [75] and Naja atra cathelicidin (NA-CATH). One of the best-known cathelicidins is Cath-BF having an α-helical structure, isolated from the venous glands of the species Bungatus fasciatus [152]. It has been shown that Cath-BF causes bacterial death through two bacterial membrane disruption mechanisms and attacking intracellular targets [152]. According to available reports, this peptide is highly active against drug-resistant clinical isolates of A. baumannii, inhibiting its growth around 12.8 μg/ml concentration [75]. ZY4 cathelicidin-BF-15 derived, a cyclic peptide stabilized by a disulfide bridge with high stability in vivo (the half-life is 1.8 h), showed excellent activity against A. baumannii, including standard clinical MDR strains with MIC values ranging between 4.6 and 9.4 μg/mL. ZY4 killed bacteria by permeabilizing the bacterial membrane showed a low propensity to induce resistance, exhibited biofilm inhibition and eradication activities, and killed persister cells [76]. The peptide NA-CATH, produced by a cobra called N. atra, possesses an α-helical structure at N-terminal and an unstructured segment at C-terminal [77, 153]. This peptide exerts antimicrobial activity through the membrane lysis by membrane thinning or transient pore formation [154] and is highly active against drug-resistant and sensitive A. baumannii strains, completely inhibiting bacterial growth at a concentration of 10 μg/ml [77, 153]. In 2018, Zhao et al. identified a novel cathelicidin (OH-CATH) from the king cobra, with its analog DOH-CATH30 found to exhibit potent microbicidal activity (MIC 1.56 to 12.5 μg/mL) against several Gram-negative and Gram-positive bacteria, including MDR A. baumannii [78]. Other cathelicidins with antimicrobial activity, identified in the venous glands, are OH-CATH30, from the venom of the cobra and mirtoxin, from Myrmecia pilosula [78, 79], presenting antimicrobial activity through inhibition of planktonic bacterial growth and biofilm, eradication of persistent bacterial cells, and inhibition of inflammatory process [76, 78].

Compounds with similar activity have been identified in the venom of some scorpion species and tested against antibiotic-resistant bacteria. Therefore, Al-Asmari et al. evaluate the in vitro antimicrobial activities of the toxins extracted from three medically necessary Saudi Scorpions. Among these, only Leiurus quinquestriatus showed significant broad-spectrum antimicrobial activity in a dose-dependent manner from 5 to 20 mg/mL, inhibiting 50.6% of growth and survival of MDR A. baumannii [80]. High antimicrobial activity was also observed for AMPs ranalexin and danalexin obtained from Rana catesbeiana [81], LS-sarcotoxin, and LS-stomoxyn (Lucilla serricata) [82], and minibactenecins (Capra hircus) [83]. However, further in vivo studies are needed to improve the pharmacokinetics of systemic administration and find solutions to avoid their degradation by proteases despite the antimicrobial activity on A. baumannii strains of these compounds.

2.1.3 Alligator cathelicidins

Alligator mississippiensis (American alligator), a member of order Crocodilia, lives in bacteria-laden environments but cannot often succumb to bacterial infections. Serum of alligators has antibacterial activity beyond that of human sérum [155], killing a wide range of pathogens, and it is believed that this activity is attributable at least partially to the presence of CAMPs in the alligator plasma and extracts [156]. A study by Barksdale et al. (2017) reported the anti-A. baumannii effect of AMPs produced by American alligator: cathelicidin called AM-CATH36 and its two fragments including AM-CATH28 and AM-CATH21 [77]. Alligator cathelicidin can inhibit the growth of both drug-resistant and sensitive A. baumannii at the 2.5 μg/ml concentration. Furthermore, two shorter fragments of this peptide can inhibit the drug-resistant A. baumannii at a 10 μg/ml concentration. The anti-A. baumannii effect of these three peptides is through membrane permeabilization. Interestingly, MDR clinical isolates of A. baumannii were more susceptible to both the AM CATH21 and AM-CATH28 peptides than the sensitive strains.

2.1.4 Wallaby antimicrobial

The marsupial AMP Wallaby antimicrobial 1 (WAM-1) is a cathelicidin isolated from the mammary gland of the Tammar wallaby (Macropus eugenii) with antibacterial and antifungal activities with high potential to combat drug-resistant pathogens [84, 157]. Spencer et al. (2018) studied the AMP LL-37 and WARM-1 effects on MDR A. baumannii, and both peptides were able to inhibit biofilm formation in all clinical isolates at some concentrations of WAM-1 effectively dispersed 24-h biofilms in most isolates tested, including MDR strains [85]. The antibacterial effects of LL-37are diminished in the presence of human serum. However, this is not the case with WAM-1. Although the mechanism of action has yet to be determined, WAM-1 has been shown in vitro to be 12 to 80 times more effective than LL-37 in its ability to kill several bacterial pathogens, including several clinical isolates of A. baumannii. Unlike LL-37, WAM-1 is not inhibited by high NaCl concentrations and does not cause hemolysis in human red blood cells (RBC), so it has the potential to be used for in vivo applications [85].

2.1.5 Bovine cathelicidins (Indolicidin and Bactenecin)

Indolicidin is a short tryptophan-rich cationic AMP encoded by a member of the cathelicidin gene family, isolated from cytoplasmic granules of the bovine neutrophils [158, 159]. Indolicidin acts by displacing divalent cations from their binding sites on the surface of the cell membrane and causes bacterial death through channel formation in the cytoplasmic membrane [88]. Indolicidin not only forms pores in the membrane but can also inhibit DNA processing enzymes [160, 161]. This peptide is among the potent anti-A. baumannii AMPs with MIC of 4–32 and 16 μg/ml against sensitive and colistin-resistant clinical isolates, respectively [86]. In a study by Giacometti et al. were investigated the in vitro activity of indolicidin and other AMPs alone and in combination with antimicrobial agents, the MIC of indolicidin against 12 MDR clinical isolates was reported as 2–64 μg/ml [87]. Isolated from bovine, ovine, and caprine neutrophil granules, Bactenecin is a short cyclic, arginine-rich cationic AMP [89] with a type I β-turn structure and forms a loop due to the disulfide bond between cysteines 3 and 11 [90]. These AMPs act by permeabilizing the cell membrane and inhibiting protein and RNA synthesis in bacteria [70]. Vila-Farres et al. (2012) reported the anti-A. baumannii effect of this peptide can inhibit sensitive and colistin-resistant strains of A. baumannii at 16 and 64 μg/ml, respectively [86].

2.2 Defensins

Defensins are an evolutionarily ancient class of AMPs present in animals, plants, and fungi involved in the immune system of living organisms and contain six (invertebrates) to eight conserved cysteine residues in their structure. They are categorized into three subfamilies of α, β, and θ-defensins [162]. Most defensins bind to the cell membrane and make pores, leading to bacterial death [163].

2.2.1 α-Defensins (HNPs and HD5)

The subfamily of human neutrophil peptides (HNPs), also known as α-defensins, are secreted and released from polymorphonuclear neutrophil (PMN) granules upon activation and are conventionally involved in microbial killing [164]. Two important CAMPs HNP-1 and HNP-2, which differ in only one initial amino acid, can inhibit the growth of the standard strain of A. baumannii ATCC 19606 at a concentration of 50 μg/ml. Interestingly, the colistin-resistant mutant of A. baumannii ATCC 19606 is much more sensitive (MIC = 3.25 μg/ml) to HNP-1 than the standard strain [86]. Human defensin 5 (HD5) has a relatively low anti-A. baumannii effect (MIC = 320 μg/ml). However, an analog called HD5d5 obtained by sequence modification presented a stronger bactericidal effect (MIC = 40 μg / ml) against A. baumannii, exerting the effect through damage to the membrane, accumulation in the cytoplasm, and reduction of catalase and superoxide dismutase activities [165, 166].

2.2.2 β-Defensins

Human β-Defensin (HBD) 2, 3 of this subfamily have anti-Acinetobacter effects. HBD-2 is primarily produced by the epithelial lining of the respiratory and urinary tracts, and engaging is more effective on MDR clinical isolates than non-MDR isolates [167]. Longer than most of the natural AMPs, HBD-3 combined helix and β structure [147]. Even though the anti-Acinetobacter bactericidal effect is inhibited by exposure to human serum, it can kill all MDR and non-MDR A. baumannii clinical isolates at 4 μg/ml during 1.5 h in the serum-free environment. Thus, this peptide has the potential to be further studied for wounds infected by A. baumannii since it demonstrated wound-healing effects [97, 168].

2.2.3 α-Helical and antiparallel β-sheet defensins

CL-defensin, belonging to the family of insect defensins, is predicted to have a characteristic N-terminal loop, an α-helix, and an antiparallel β-sheet, which was supported by circular dichroism spectroscopy [95]. In addition, this peptide induces pore formation in other Gram-positive bacteria and causes a small amount of membrane permeabilization in A. baumannii [95].

2.3 Frog antimicrobial peptides

2.3.1 Magainin and pexiganan (its analog)

The Magainin-1 and 2 are cationic, α-helical, and amphipathic AMPs ionophores isolated from the skin of the African clawed frog (Xenopus laevis) [168, 169]. The primary mechanism of antimicrobial activity is probably pore formation in outer and inner membranes, although the exact mechanism of action is not yet precise [98, 170]. Despite both have anti-Acinetobacter training, Magainin-2 is much stronger and able to inhibit the growth of sensitive and MDR strains of A. baumannii at 4.9–64 μg/ml, while reported as 256 μg/ml for Magainin-1 [86, 98]. Magainin-2 has some advantages, such as anticancer effect, stability at physiological salt concentrations, lack of hemolytic activity, and toxicity for mammalian cells [98]. Furthermore, Magainin-2 can inhibit and eliminate the biofilm of A. baumannii [98]. Pexiganan AMP or MSI-78 is a synthetic analog of Magainin-2 with a potent and broad spectrum of action [171, 172]; it kills bacteria by forming toroidal pores in their cell membranes [172, 173]. Several studies have been performed on anti-Acinetobacter activity due to its being highly active against Acinetobacter. Pexiganan can inhibit the growth of MDR and sensitive clinical isolates of A. baumannii at a concentration of 1–8 μg/ml [100, 101, 174]. Jáskiewicz et al. studied the antimicrobial activity of eight peptides on A. baumannii ATCC 19606 reference strains. Among these, CAMEL and pexiganan showed potent antimicrobial and anti-biofilm activity [102].

2.3.2 Brevinin-2 related peptide (B2RP)

B2RP is an α-helical AMP isolated from the skin secretions of the mink frog Rana septentrionalis [175] and carpenter frog Rana virgatipes [176]. This peptide forms an α-helical structure adjacent to the target cell, resulting in the perturbation of the phospholipid bilayer that may lead to growth inhibition of bacterial death, and the application of this peptide for systemic use is limited due to the moderate toxicity for human red blood cells [177]. B2RP inhibited the growth of a susceptible strain of A. baumannii at 29 μg/ml concentration but inhibited the MDR isolates more efficiently at 7–13.9 μg/ml [103]. The analogs of these peptides (D4K, K16A, L18K) resulted in twofolds higher anti-A. baumannii activity and much lower hemolytic activity [103]. A study reported that the analog of B2RP with D4K substitution inhibited sensitive and colistin-resistant [103] and XDR isolates of A. baumannii [105].

2.3.3 B2RP-ERa

B2RP-ERa is a cationic AMP from the Brevinin family isolated from the skin of the Asian frog Hylarana erythraea [106, 178]. Shorter and with lower molecular weight, B2RP-ERa is structurally similar to B2RP. B2RP-ERa is an anti-inflammatory peptide with no toxic effect on peripheral blood mononuclear cells [179] with low hemolytic activity [178], which could inhibit the growth of sensitive and drug-resistant Acinetobacter strains at 8–32 and 8–64 μg/ml, respectively [104, 106].

2.3.4 Alyteserins

Alyteserins are a class of cationic AMPs, which firstly reported their presence in norepinephrine-stimulated skin secretions of the midwife toad [180]. However, initial studies show that Alyteserin-1c has more significant inhibitory activity against Gram-negative bacteria, while Alyteserin-2a is more active against Gram-positive bacteria [180], the anti-A. baumannii effects of these Alyteserins have already been proven [107, 108]. Alyteserin-1c is a cationic α-helical AMP with low hemolytic activity on human red blood cells firstly isolated from Alytes obstetricans [107, 180, 181]. The MIC and MBC against clinical isolates of MDR A. baumannii have been reported as 11.3–22.6 μg/ml [107]. Substitution of E4K on this AMP reduced the hemolytic activity, and enhanced the antimicrobial and cationic activity [107]. The analog [E4K] inhibits the growth of colistin-sensitive, colistin-resistant, and XDR A. baumannii isolates at concentrations of 4–16 μg/ml, 4–16 μg/ml [104], and 8–64 μg/ml, respectively [105]. Alyteserin-2a is also a tiny α-helical AMP that displays relatively weak antimicrobial and hemolytic activities. Despite its anti-A. baumannii potential was not high mainly, some structural changes resulted in lower toxicity against human erythrocytes and higher bactericidal effect (4–8 folds) against MDR isolates with MIC of 6.8–13.6 μg/ml [108].

2.3.5 Peptide glycine-leucine-amide

AM1 (PGLa-AM1) PGLa-AM1 is another Anti-Acinetobacter AMP isolated from the frog Xenopus amieti. In addition to the low hemolytic activity, it is also active against other pathogens, including E. coli and S. aureus [104, 106, 109], and can kill sensitive and colistin-resistant A. baumannii isolates at 16–128 μg/ ml concentration [104].

2.3.6 Caerulein precursor fragment (CPF)

CPF-AM1 is a cationic AMP firstly isolated from X. amieti [110]. This peptide is capable of bacterial binding LPS and has activity against Gram-negative and Gram-positive bacteria, primarily oral and respiratory pathogens, with advantages such as low hemolytic activity and lack of toxicity against fibroblast cells [109]. This anti-A. baumannii peptide inhibits the growth of sensitive and colistin-resistant strains at 16–128 and 4–128 μg/ml, respectively [104, 114]. CPF-B1, isolated from Marsabit clawed frog Xenopus borealis, is another anti-A. baumannii member of this family with low hemolytic activity. This peptide inhibits MDR A. baumannii clinical isolates at concentrations of 11.4–22.8 μg/ml [112]. Finally, CPF-C1 is a peptide member of this family with proved anti-A. baumannii effect with inhibitory activity against the strain at 5 μg/ml concentration [111].

2.3.7 Hymenochirins

Hymenochirins are a class of AMPs produced by two frogs of Pseudhymenochirus merlini and Hymenochirus boettgeri with letters P and B in the second part name of these peptides indicating the producing species of the peptide, respectively [37, 182]. Hymenochirin-1B is a cationic, α-helical amphibian host-defense peptide with antimicrobial, anticancer, and immunomodulatory properties. This peptide has anti-A. baumannii properties against MDR isolates with MIC of 19.1 μg/ml [113]. Among the analogs of hymenochirin-1B obtained by amino acid substitution method, [E6k and D9k] hymenochirin-1B reduced human erythrocytes’ toxicity and showed 3.9-folds higher activity against A. baumannii. [E6k and D9k] hymenochirin-1B is active against both MDR and XDR isolates and could inhibit the growth of these isolates at 4.9 μg/ml concentration [113]. Hymenochirin-1 Pa is another cationic member of this family with moderate hemolytic activity. This peptide inhibited the growth of XDR A. baumannii isolates at 7.5–15 μg/ml concentration [114, 182].

2.3.8 XT-7

XT-7 was first isolated from norepinephrine-stimulated skin secretions of Xenopus tropicalis [183]. The activity anti-Acinetobacteof this peptide was first reported against A. baumannii Euroclone I NM8 strain (MIC = 22.2 μg/ml) [111]. Later, the amino acid substitution of lysine at position 4 [G4K] increased the therapeutic index [115] principally. Subsequent studies were based on this new analog that inhibited sensitive and drug-resistant A. baumannii strains at concentrations of 4–32 and 4–64 μg/ml, respectively [104].

2.3.9 Buforins

Buforin II is a potent antimicrobial peptide derived from Burforin I, isolated from the stomach tissue of the Asian toad Bufo gargarizans [184]. It causes bacterial death by crossing the membrane, binding to intracellular targets, including DNA and RNA, and inhibiting cellular functions [116]. This peptide has a potent anti-Acinetobacter activity since it can hinder the growth of both sensitive and resistant isolates of A. baumannii at concentrations of 0.25–39 μg/ml [87, 98]. Buforin II alone or in combination with an antibiotic showed highly potent on A. baumannii sepsis treatment in a rat model [104].

2.4 Melittin

Melittin is a cationic amphipathic α-helical AMP isolated from the venom (approximately 50% of the dry weight) of the European honeybee (Apis mellifera) [185] with numerous reported properties such as antifungal [186], antiparasitic [187], antibacterial [185], antiviral, and anticancer properties [188]. The primary mechanism of melittin action is the membrane lysis through pore formation (a carpet-like mechanism) [189]. This potent anti-Acinetobacter peptide inhibits MDR and XDR clinical isolates at 0.125–2 μg/ml concentration [118, 119]. A study demonstrated that topical administration of melittin at concentrations of 16 and 32 μg/mL in mice killed 93.3% and 100% of an XDR A. baumannii on a third-degree burned area, respectively [118]. No toxicity was observed on the injured or healthy derma and circulating red blood cells in the examined mice. Recently, a study that evaluated the melittin against Brazilian clinical strains revealed that most strains were susceptible, except for one pan drug-resistant strain [190].

2.5 Cecropins

Cecropins, the lytic peptides, were initially isolated from the hemolymph of the giant silk moth, Hyalophora cecropia, and possess antibacterial and anticancer activity in vitro [191, 192]. The primary antimicrobial mechanism of cecropins is membrane lysis [193]. Cecropin A is a cationic amphipathic α-helical AMP that can induce apoptosis by oxidative stress in addition to attacking the membrane [194]. This peptide has potent antimicrobial activity against A. baumannii, inhibiting MDR clinical isolates at 0.5–32 μg/ml [99]. Vila-Farres et al. reported that this peptide inhibited the growth of sensitive and colistin-resistant strains of A. baumannii at 32 and 256 μg/ ml, respectively [86]. A pilot study that evaluated the viability of Caenorhabditis elegans infected by A. baumannii in the presence of 68 insect-derived AMPs identified 15 cecropin or cecropin-like peptides that prolonged the survival of worms infected with A. baumannii [121]. Interestingly, the direct investigation of the anti-Acinetobacter effect also showed that these 15 AMPs could inhibit the growth of A. baumannii at 4.5 to over 20 μg/ml concentrations. BR003-cecropin A, isolated from Aedes aegypti, is the most active member of this group. This peptide inhibited sensitive and MDR A. baumannii strains at 4.5 μg/ml [100]. Musca domestica cecropin (Mdc) isolated from the larvae of a housefly inhibits both standard (ATCC 19606) and MDR strains of A. baumannii at 4 μg/ml with high speed (half an hour) [122]. Cecropin P1, an AMP isolated from Ascaris suum of pig intestine, showed high activity against colistin-sensitive A. baumannii with MIC at 1.6 μg/ml. In contrast, there was less activity against the colistin-resistant strains with MIC >25 μg/ml [86].

Other peptides that showed great activity against susceptible MDR and extensively drug-resistant (XDR) A. baumannii strains were Cecropin-4, an α-helical synthetic AMP [124], and CAMEL, a hybrid AMP consisting of cecropin from H. cecropia and melittin from Apis melífera [102]. In addition, AMPs with activity against biofilms have been observed in cecropins identified in M. domestica [124], myxinidin isolated from Myxine glutinosa [104], and in the naturally occurring AMP complex isolated from the maggots of blowfly Calliphora vicina (Diptera, Calliphoridae) named FLIP7 (Fly Larvae Immune Peptides 7) [126].

2.6 Mastoparan

Mastoparan is a small cationic amphipathic α-helical AMP isolated from the hornet venom of Vespula lewisii [195, 196] with a robust anti-Acinetobacter activity. However, the anti-acinetobacter solid activity, the high hemolytic activity, and toxic effects affected highly therapeutic applications [197]. Mastoparan inhibited the growth of a sensitive wild-type A. baumannii ATCC 19606 and a colistin-resistant A. baumannii ATCC 19606 mutant at 4 and 1 μg/ml, respectively. This study also used 14 colistin-susceptible A. baumannii clinical isolates and 13 pan-resistant A. baumannii strains isolated in a hospital outbreak [198] and reported the MIC of 1–16 and 2–8 μg/ ml for sensitive and colistin-resistant isolates, respectively [86]. Mastoparan-AF (MP-AF), isolated from the hornet venom of Vespa affinis, also showed effective antimicrobial activity with MICs ranging from 2 to 16 μg/ml against MDR A. baumannii isolates [129]. Analogs of mastoparan were made to increase the stability of the peptide in serum. These analogs had an equal inhibitory effect with mastoparan against XDR A. baumannii strains (4 μg/ml); in addition, it showed stability in the presence of human serum for more than 24 h [86].

2.7 Histatins

Histatins belong to a distinct family of at least 12 low-molecular weight, histidine-rich cationic, salivary gland peptides with antimicrobial effect through the plasma membrane disruption [199]. Histatin-8, known as hemagglutination-inhibiting peptide [200], was the only member of this group that showed antimicrobial activity against A. baumannii, inhibiting the growth of both sensitive standard strains colistin-resistant mutant A. baumannii ATCC 19606 at 32 μg/ml [86].

2.8 Dermcidins

Dermcidin is an anionic AMP encoded by the DCD gene in humans essentially produced in eccrine sweat glands, secreted into a sweat, and further transported to the skin’s epidermal surface [130, 201]. It has two parts; N-terminal peptide promotes neural cell survival under severe oxidative stress conditions called DCD-1 L [130]. DCD-1 L, a C-terminal peptide with the net electric charge of −2, is the only anionic anti-Acinetobacter natural AMP found in the literature that shows partial helicity in solution [130, 182]. Interestingly, in exposure to this AMP, the PDR A. baumannii isolates are twice more susceptible as XDR isolates and the standard strain (ATCC 19606) (MIC = 8 μg/ ml) [131].

2.9 Tachyplesin III

Tachyplesin III, isolated from the hemolymph of the Southeast Asian horseshoe crabs Tachypleus gigas and Carcinoscorpius rotundicauda, consists of 17 amino acids with two disulfide bridges and is a representative antimicrobial peptide with a cyclic β-sheet structure. However, its potential toxicity hampers its use in mammalian cells [202]. Nevertheless, Tachyplesin III could inhibit the XDR A. baumannii strains (8–16 μg/ml) and at 2 × MIC, eliminating the XDR A. baumannii strains [203].

2.10 Computationally designed antimicrobial peptide

The biosynthesis of AMPs can be a starting point for obtaining AMPS with functions similar to natural ones, being an attractive therapeutic option for preventing and controlling infections. In this sense, bioinformatics and computer science have been widely used in various aspects in many studies of A. baumannii, such as design evaluation of AMPs [136, 204, 205, 206, 207, 208], which includes two general principles that increased antimicrobial activity and reduced toxicity against eukaryotic cells [209, 210]. As an example of synthetic AMPs, we have stapled AMP [137] and PNA (RXR) 4XB, an antisense nucleic acid peptide compound [138] with intense bactericidal activity. The synthetic RR is a small α-helical AMP with fast bactericidal activity capable of retaining the antimicrobial property at physiological concentrations of NaCl and MgCl2 [132]. The anti-A. baumannii effect of RR against sensitive and MDR strains inhibits the growth at 25–99 μg/ml concentration. Two new analogs of this peptide were introduced with much stronger anti-A. baumannii properties than RR, and the AMPs RR2 and RR4 inhibit the growth of sensitive and drug-resistant strains (3–6 μg/ml) [211]. The peptide DP7 inhibits the growth of antibiotic-resistant A. baumannii strains at 4–16 μg/ml concentration, and the synergistic effects were showed after simultaneous treatment of some drug-resistant A. baumannii isolates with DP7 and antibiotics such as amoxicillin, azithromycin, and vancomycin [133]. Zhang et al. showed that DP7 invades the microbial cell through various pathways after sequencing the transcriptome of the bacteria exposed to this peptide [134]. Omega76 is a cationic AMP with an α-helical structure, causing death in A. baumannii through membrane disruption. This peptide was designed based on the maximum common subgraph of helices and further introduced as an appropriate alternative for colistin due to its high anti-A. baumannii activity against carbapenem and tigecycline-resistant isolates (MBC = 2–8 μg/ml) and lack of toxicity in the mouse model [135].


3. Resistance to AMPS

Although AMPs have a low likelihood to select for resistance, similar to the conventional antibiotics, another challenge is represented by the numerous reports describing the development of resistance mechanisms against some AMPs, including proteolytic degradation or sequestration by secreted proteins, impedance by exopolymers, and biofilm matrix molecules, circumvention of attraction by cell surface/membrane alteration, and export by efflux pumps [212, 213, 214, 215, 216]. The development of resistance to colistin by A. baumannii following long-term clinical application was observed [217, 218]. In A. baumannii stable colistin resistance was also observed following direct plating with the complete loss of LPS production due to the inactivation of one of three genes involved in lipid A biosynthesis (lpxA, lpxD, or lpxC). Resistance to colistin is an important clinical issue, considering that colistin is a last-resort drug used to treat MDR nosocomial pathogens [218, 219, 220]. Several mechanisms have been reported responsible for resistance to AMPs, including expression of efflux pumps, increased secretion of proteolytic enzymes, and surface charge modification to avoid membrane-peptide electrostatic interactions [213, 221, 222].

For delivering the AMPs, several nanocarriers were developed, which may help avoid the low bioavailability, proteolysis, or susceptibility and toxicity associated with APMs [223, 224]. Changes in the molecular structure, modifications of biochemical characterization, and combination with common antibiotics have been reported to reduce AMP resistance [214]. The aprotinin is the first inhibitor identified to inhibit AMP resistance in multiple pathogens [225].


4. Conclusion(s)

A. baumannii is one of the ESKCAPE pathogens responsible for nosocomial and community-acquired infections, with the incidence of MDR and virulent clones increasingly worldwide. The enormous adaptability of A. baumannii, as well as the remarkable ability to acquire determinants of resistance, allied to your innate ability to form biofilms, contributes to the inefficiency of most current therapeutic strategies, determining the transition to the “post-antibiotic era” and highlighting the necessity to develop new therapeutic approaches. In this context, natural and synthetic AMPs emerge as potential next-generation antibiotics to mitigate a wide array of microbial infections, including those caused by MDR A. baumannii strains. Moreover, the antimicrobial activity of these peptides can be effectively increased by minor modifications through the development of computer science and bioinformatics. The synthetic AMPs present a promising solution to overcome the drawbacks of using natural AMPs. They contain critical features based on natural AMPs, with slight modifications to achieve higher antimicrobial efficiency and improved chemical stability. In this research, we observed the main properties of anti-A. baumannii peptides with some common characteristics, such as 1. The α-helical structure was predominant. 2. Most peptides have a positive charge, and in many cases, there is a direct relationship between an increased positive charge and your activity. 3. The action mechanisms of these peptides are direct membrane attack and intracellular targeting or both simultaneously. Unfortunately, considerable experimental data describe how bacteria can develop resistance to AMPs, such as colistin and polymyxin B in A. baumannii. Since AMPS are considered potential novel antimicrobial drugs, understanding the mechanism of bacterial resistance to direct killing of AMPS is of great significance.


Conflict of interest

The authors declare no conflict of interest.


Notes/thanks/other declarations

We thank D. Guilherme Curty Lechuga by the drawing of figures 1 and 2 of this chapter.


  1. 1. O’Neill J. Tackling Drug-Resistance Infections Globally: Final Report and Recommendations. The Review on Antimicrobial Resistance. London, UK: Government of the United Kingdom; 2016. 84 p
  2. 2. Tacconelli E, Carrara A, Savoldi S, Harbarth M, Mendelson DL, Monnet C, et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. The Lancet Infectious Diseases. 2018;18(3):318-327
  3. 3. Lewis K. Persister cells, dormancy, and infectious disease. Nature Reviews. Microbiology. 2007;5(1):48-56
  4. 4. Lewis K. Persister cells. Annual Review of Microbiology. 2010;64:357-372. DOI: 10.1146/annurev.mi cro.112408.134306
  5. 5. Fernández L, Breidenstein EBM, Hancock REW. Importance of adaptive and stepwise changes in the rise and spread of antimicrobial resistance. In: Keen P, Monforts M, editors. Antimicrobial Resistance in the Environment. Hoboken, New Jersey, EUA: Wiley-Blackwell; 2011. pp. 43-71. ISBN: 978-1-118-15623-0
  6. 6. Olivares J, Bernardini A, Garcia-Leon G, Corona F, Sanchez MB, Martinez JL. The intrinsic resistome of bacterial pathogens. Frontiers in Microbiology. 2013;30(4):103
  7. 7. Lewis K, Shan Y. Persister Awakening. Molecular Cell. 2016;63(1):3-4
  8. 8. Conlon BP, Rowe SE, Gandt AB, Nuxoll AS, Donegan NP, Zalis EA, et al. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nature Microbiology. 2016;1:16051
  9. 9. Shan Y, Brown Gandt A, Rowe SE, Deisinger JP, Conlon BP, Lewis K. ATP-dependent persister formation in Escherichia coli. MBio. 2017;8(1):e02267-e02216
  10. 10. Magana M, Sereti C, Ioannidis A, Mitchell CA, Ball AR, Magiorkinis E, et al. Options and limitations in clinical investigation of bacterial biofilms. Clin Microbiol Ver. 2018;31(3):e00084-e00016
  11. 11. Cameron DR, Shan Y, Zalis EA, Isabella V, Lewis K. A genetic determinant of persister cell formation in bacterial pathogens. Journal of Bacteriology. 2018;200(17):e00303-e00318
  12. 12. Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: A global, multifaceted phenomenon. Pathog Global Health. 2015;109(7):309-318
  13. 13. Holmes AH, Moore LSP, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet. 2016;387(10014):176-187
  14. 14. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE. Infectious Diseases. 2008;197(8):1079-1081
  15. 15. Friedman ND, Temkin E, Carmeli Y. The negative impact of antibiotic resistance. Clinical Microbiology and Infection. 2016;22(5):416
  16. 16. Eze EC, Chenia HY, El Zowalaty ME. Acinetobacter baumannii biofilms: Effects of physicochemical factors, virulence, antibiotic resistance determinants, gene regulation, and future antimicrobial treatments. Infect Drug Resist. 2018;15(11):2277-2299
  17. 17. Cosgaya C, Mari-Almirall M, van Assche A, Fernandez-Orth D, Mosqueda N, Telli M, et al. Acinetobacter dijkshoorniae sp. nov., a member of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex mainly recovered from clinical samples in different countries. International Journal of Systematic and Evolutionary Microbiology. 2016;66(10):4105-4111
  18. 18. Nemec A, Krizova L, Maixnerova M, Sedo O, Brisse S, Higgins PG. Acinetobacter seifertii sp. nov., a member of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolated from human clinical specimens. International Journal of Systematic and Evolutionary Microbiology. 2015;63(Pt 3):934-942
  19. 19. Vijayakumar S, Biswas I, Veeraraghavan B. Accurate identification of clinically important Acinetobacter spp.: An update. Future Sci AO. 2019;5(6):FSO395
  20. 20. Chen TL, Lee YT, Kuo SC, Yang SP, Fung CP, Lee SD. Rapid identification of Acinetobacter baumannii, Acinetobacter nosocomialis, and Acinetobacter pittii with a multiplex PCR assay. Journal of Medical Microbiology. 2014;63(Pt 9):1154-1159
  21. 21. Marí-Almirall M, Cosgaya C, Higgins PG, Van Assche A, Telli M, Huys G, et al. MALDI-TOF/MS identification of species from the Acinetobacter baumannii (ab) group revisited: Inclusion of the novel a. seifertii and A. dijkshoorniae species. Clinical Microbiology and Infection. 2017;23(3):210.e1-210.e9
  22. 22. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: Emergence of a successful pathogen. Clinical Microbiology Reviews. 2008;21(3):538-582
  23. 23. Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: Multidrug-resistant Acinetobacter baumannii. Nature Reviews. Microbiology. 2007;5(12):939-951
  24. 24. Garnacho-Montero J, Timsit JF. Managing Acinetobacter baumannii infections. Current Opinion in Infectious Diseases. 2019;32(1):69-76
  25. 25. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pan drug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection. 2012;18(3):268-281
  26. 26. Xie R, Zhang XD, Zhao Q, Peng B, Zheng J. Analysis of global prevalence of antibiotic resistance in Acinetobacter baumannii infections disclosed a faster increase in OECD countries. Emerg. Microb. Infect. 2018;7(1):1-10
  27. 27. Willyard C. The drug-resistant bacteria that pose the greatest health threats. Nature. 2017;543(7643):15
  28. 28. Barth VCJ, Rodrigues BÁ, Bonatto GD, Gallo SW, Pagnussatti VE, Ferreira CAS, et al. Heterogeneous persister cells formation in Acinetobacter baumannii. PLoS One. 2013;8(12):e84361
  29. 29. Lukovic B, Gajic I, Dimkic I, Kekic D, Zornic S, Pozder T, et al. The first nationwide multicenter study of Acinetobacter baumannii recovered in Serbia: Emergence of OXA-72, OXA-23 and NDM-1-producing isolates. Antimicrobial Resistance and Infection Control. 2020;9(1):101
  30. 30. Isler B, Doi Y, Bonomo RA, Paterson DL. New treatment options against carbapenem-resistant Acinetobacter baumannii infections. Antimicrobial Agents Chemother. 2019;63(1):e01110-e01118
  31. 31. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at: [Accessed in July 2021]
  32. 32. Domalaon R, Zhanel GG, Schweizer F. Short antimicrobial peptides and peptide scaffolds as promising antibacterial agents. Current Topics in Medicine Chemistry. 2016;16(11):1217-1230
  33. 33. Vrancianu CO, Gheorghe I, Czobor IB, Chifiriuc MC. Antibiotic resistance profiles, molecular mechanisms, and innovative treatment strategies of Acinetobacter baumannii. Microorganisms. 2020;8(6):935
  34. 34. Falanga A, Galdiero S. Emerging therapeutic agents on the basis of naturally occurring antimicrobial peptides. In: SPR, Amino Acids, Peptides and Proteins. Vol. 42. Cambridge, UK: Royal Society of Chemistry; 2018. pp. 190-227. ISBN: 978-1-78801-002-3
  35. 35. Kang HK, Kim C, Seo CH, Park Y. The therapeutic applications of antimicrobial peptides (AMPs): A patent review. Journal of Microbiology. 2017;55(1):1-12
  36. 36. Pasupuleti M, Schmidtchen A, Malmsten M. Antimicrobial peptides: Key components of the innate immune system. Critical Reviews in Biotechnology. 2012;32(2):143-171
  37. 37. Wang G, Li X, Wang Z. APD3: The antimicrobial peptide database as a tool for research and education. Nucleic Acids Research. 2015;44(D1):D1087-D1093
  38. 38. Neshani A, Zare H, Akbari Eidgahi MR, Chichaklu AH, Movaqar A, Ghazvini K. Review of antimicrobial peptides with anti-helicobacter pylori activity. Helicobacter. 2019;24(1):e12555
  39. 39. Mansour SC, Pena OM, Hancock REW. Host defense peptides: front-line immunomodulators. Trends in Immunology. 2014;35(9):443-450
  40. 40. Falanga A, Lombardi L, Franci G, Vitiello M, Iovene MR, Morelli G, et al. Marine antimicrobial peptides: Nature provides templates for the design of novel compounds against pathogenic bacteria. International Journal of Molecular Sciences. 2016;17(5):785
  41. 41. Moretta A, Scieuzo C, Petrone AM, Salvia R, Manniello MD, Franco A, et al. Antimicrobial peptides: A new hope in biomedical and pharmaceutical fields. Frontiers in Cellular and Infection Microbiology. 2021;11:668632
  42. 42. Haney EF, Brito-Sánchez Y, Trimble MJ, Mansour SC, Cherkasov A, Hancock REW. Computer-aided discovery of peptides that specifically attack bacterial biofilms. Scientific Reports. 2018;8(1):1871
  43. 43. Govender T, Dawood A, Esterhuyse AJ, Katerere DR. Antimicrobial properties of the skin secretions of frogs. South African Journal of Science. 2012;108:25-30
  44. 44. Pfalzgraff A, Brandenburg K, Weindl G. Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Frontiers in Pharmacology. 2018;9:281
  45. 45. Neshani A, Zare H, Akbari Eidgahi MR, Khaledi A, Ghazvini K. Epinecidin-1, a highly potent marine antimicrobial peptide with anticancer and immunomodulatory activities. BMC. Pharmacology & Toxicology. 2019;20(1):33. DOI: 10.1186/s40360-019-0309-7
  46. 46. Neshani A, Tanhaeian A, Zare H, Eidgahi MRA, Ghazvini K. Preparation and evaluation of a new biopesticide solution candidate for plant disease control using pexiganan gene and Pichia pastoris expression system. Gene Rep. 2019;17:100509
  47. 47. Fan L, Sun J, Zhou M, Zhou J, Lao X, Zheng H. DRAMP: A comprehensive data repository of antimicrobial peptides. Scientific Reports. 2016;14(6):24482
  48. 48. Kumar P, Kizhakkedathu JN, Straus SK. Antimicrobial peptides: Diversity, mechanism of action, and strategies to improve the activity and biocompatibility in vivo. Biomolecules. 2018;8(1):4
  49. 49. Zhang LJ, Gallo RL. Antimicrobial peptides. Current Biology. 2016;26(1):R14-R19
  50. 50. Zhang G, Sunkara LT. Avian antimicrobial host defense peptides: From biology to therapeutic applications. Pharmaceuticals. 2014;7(3):220
  51. 51. Cruz J, Ortiz C, Guzman F, Fernandez-Lafuente R, Torres R. Antimicrobial peptides: Promising compounds against pathogenic microorganisms. Current Medicinal Chemistry. 2014;21(20):2299
  52. 52. Epand RM, Walker C, Epand RF, Magarvey NA. Molecular mechanisms of membrane targeting antibiotics. Biochimica et Biophysica Acta - Biomembranes. 2016;1858:980-987
  53. 53. Andersson DI, Hughes D, Kubicek-Sutherland JZ. Mechanisms and consequences of bacterial resistance to antimicrobial peptides. Drug Resist. Updated. 2016;26:43-57
  54. 54. Ehrenstein G, Lecar H. Electrically gated ionic channels in lipid bilayers. Quarterly Reviews of Biophysics. 1977;10:1-34
  55. 55. Brogden KA. Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nature Reviews. Microbiology. 2005;3:238-250
  56. 56. Breukink E, de Kruijff B. The lantibiotic nisin, a special case or not? Biochimica et Biophysica Acta. 1999;1462:223-234
  57. 57. Wimley WC. Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chemical Biology. 2010;5:905-917
  58. 58. Rapaport D, Shai Y. Interaction of fluorescently labeled pardaxin and its analogs with lipid bilayers. The Journal of Biological Chemistry. 1991;266:23769-23775
  59. 59. Shai Y, Bach D, Yanovsky A. Channel formation properties of synthetic pardaxin and analogs. The Journal of Biological Chemistry. 1990;265:20202-20209
  60. 60. Uematsu N, Matsuzaki K. Polar angle as a determinant of amphipathic α-helix-lipid interactions: A model peptide study. Biophysical Journal. 2000;79:2075-2083
  61. 61. Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacological Reviews. 2003;55:27-55
  62. 62. Lee T-H, Hall KN, Aguilar M-I. Antimicrobial peptide structure and mechanism of action: A focus on the role of membrane structure. Current Topics in Medicinal Chemistry. 2016;16:25-39
  63. 63. Cheng JTJ, Hale JD, Elliot M, Hancock REW, Straus SK. Effect of membrane composition on antimicrobial peptides aurein 2.2 and 2.3 from Australian southern bell frogs. Biophysical Journal. 2009;96:552-565
  64. 64. Sparr E, Ash WL, Nazarov PV, Rijkers DTS, Hemminga MA, Tieleman DP, et al. Self-association of transmembrane-helices in model membranes. The Journal of Biological Chemistry. 2005;280:39324-39331
  65. 65. Cheng JTJ, Hale JD, Elliott M, Hancock REW, Straus SK. The importance of bacterial membrane composition in the structure and function of aurein 2.2 and selected variants. Biochimica et Biophysica Acta - Biomembranes. 2011;1808:622-633
  66. 66. Shai Y. Mode of action of membrane-active antimicrobial peptides. Biopolymers. 2002;66:236-248
  67. 67. Fernandez DI, Le Brun AP, Whitwell TC, Sani M-A, James M, Separovic F. The antimicrobial peptide aurein 1.2 disrupts model membranes via the carpet mechanism. Physical Chemistry Chemical Physics. 2012;14:15739
  68. 68. Sitaram N, Nagaraj R. Interaction of antimicrobial peptides with biological and model membranes: Structural and charge requirements for activity. Biochimica et Biophysica Acta. 1999;1462:29-54
  69. 69. Rozek A, Friedrich CL, Hancock RE. Structure of the bovine antimicrobial peptide indolicidin bound to dodecyl phosphocholine and sodium dodecyl sulfate micelles. Biochemistry. 2000;39:15765-15774
  70. 70. Gee ML, Burton M, Grevis-James A, Hossain MA, McArthur S, Palombo EA, et al. Imaging the action of antimicrobial peptides on living bacterial cells. Scientific Reports. 2013;3:1557
  71. 71. Choi H, Rangarajan N, Weisshaar JC. Lights, camera, action! Antimicrobial peptide mechanisms imaging in space and time. Trends in Microbiology. 2016;24:111-122
  72. 72. Manzini MC, Perez KR, Riske KA, Bozelli JC, Santos TL, da Silva MA, et al. Peptide: Lipid ratio and membrane surface charge determine the mechanism of action of the antimicrobial peptide BP100. Conformational and functional studies. Biochimica et Biophysica Acta - Biomembranes. 2014;1838:1985-1999
  73. 73. Feng X, Sambanthamoorthy K, Palys T, Paranavitana C. The human antimicrobial peptide LL-37 and its fragments possess both antimicrobial and antibiofilm activities against multidrug-resistant Acinetobacter baumannii. Peptides. 2013;49:131-137
  74. 74. de Breij A, Riool M, Cordfunke RA, Malanovic N, de Boer L, Koning RI, et al. The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms. Sci Transl. 2018;10(423):eaan4044
  75. 75. Tajbakhsh M, Akhavan MM, Fallah F, Karimi A. A recombinant snake cathelicidin derivative peptide: Antibiofilm properties and expression in Escherichia Coli. Biomolecules. 2018;8(4):118
  76. 76. Mwangi J, Yin Y, Wang G, Yang M, Li Y, Zhang Z, et al. The antimicrobial peptide ZY4 combats multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii Infection. Proc Natl Acad Sci. USA. 2019;116(52):26516-26522
  77. 77. Barksdale SM, Hrifko EJ, van Hoek ML. Cathelicidin antimicrobial peptide from Alligator mississippiensis has antibacterial activity against multi-drug resistant Acinetobacter baumanii and Klebsiella pneumoniae. Developmental and Comparative Immunology. 2017;70:135-144
  78. 78. Zhao F, Lan XQ, Du Y, Chen PY, Zhao J, Zhao F, et al. King cobra peptide OH-CATH30 as a potential candidate drug through clinic drug-resistant isolates. Zoological Research. 2018;39(2):87-96
  79. 79. Dekan Z, Headey SJ, Scanlon M, Baldo BA, Lee TH, Aguilar MI, et al. ∆-Myrtoxin-Mp1a is a helical heterodimer from the venom of the jack jumper ant that has antimicrobial, membrane-disrupting, and nociceptive activities. Angewandte Chemie (International Ed. in English). 2017;56(29):8495-8499
  80. 80. Al-Asmari AK, Alamri MA, Almasoudi AS, Abbasmanthiri R, Mahfoud M. Evaluation of the in vitro antimicrobial activity of selected Saudi scorpion venoms tested against multidrug-resistant micro-organisms. J Glob Antimicrob Resist. 2017;10:14-18
  81. 81. Domhan C, Uhl P, Kleist C, Zimmermann S, Umstätter F, Leotta K, et al. Replacement of L-amino acids by d-amino acids in the antimicrobial peptide ranalexin and its consequences for antimicrobial activity and biodistribution. Molecules. 2019;24(16):2987
  82. 82. Hirsch R, Wiesner J, Marker A, Pfeifer Y, Bauer A, Hammann PE, et al. Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR gram-negative bacteria. The Journal of Antimicrobial Chemotherapy. 2019;74(1):96-107
  83. 83. Shamova OV, Orlov DS, Zharkova MS, Balandin SV, Yamschikova EV, Knappe D, et al. Minibactenecins ChBac7.Nα and ChBac7. Nβ—Antimicrobial peptides from leukocytes of the goat Capra hircus. Acta Naturae. 2016;8(3):136-146
  84. 84. Spencer JJ, Pitts RE, Pearson RA, King LB. The effects of antimicrobial peptides WAM-1 and LL-37 on multidrug-resistant Acinetobacter baumannii. Pathogens and Disease. 2018;76(2):fty007
  85. 85. Vila-Farres X, De La Maria CG, López-Rojas R, Pachón J, Giralt E, Vila J. In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii. Clinical Microbiology and Infection. 2012;18(4):383-387
  86. 86. Giacometti A, Cirioni O, Del Prete MS, Barchiesi F, Paggi AM, Petrelli E, et al. Comparative activities of polycationic peptides and clinically used antimicrobial agents against multidrug-resistant nosocomial isolates of Acinetobacter baumannii. The Journal of Antimicrobial Chemotherapy. 2000;46(5):807-810
  87. 87. Falla TJ, Karunaratne DN, Hancock RE. Mode of action of the antimicrobial peptide indolicidin. The Journal of Biological Chemistry. 1996;271(32):19298-19303
  88. 88. Romeo D, Skerlavaj B, Bolognesi M, Gennaro R. Structure and bactericidal activity of an antibiotic dodecapeptide purified from bovine neutrophils. The Journal of Biological Chemistry. 1988;263(20):9573-9575
  89. 89. Wu M, Hancock RE. Interaction of the cyclic antimicrobial cationic peptide bactenecin with the outer and cytoplasmic membrane. The Journal of Biological Chemistry. 1999;274(1):29-35
  90. 90. Skerlavaj B, Romeo D, Gennaro R. Rapid membrane permeabilization and inhibition of vital functions of gram-negative bacteria by bactenecins. Infection and Immunity. 1990;58(11):3724-3730
  91. 91. Shamova O, Orlov D, Stegemann C, Czihal P, Hoffmann R, Brogden K, et al. ChBac34: A novel proline-rich antimicrobial peptide from goat leukocytes. Int J Pept Res Therapy. 2009;15(1):31-42
  92. 92. Seefeldt AC, Graf M, Pérébaskine N, Nguyen F, Arenz S, Mardirossian M, et al. Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome. Nucleic Acids Research. 2016;44(5):2429-2438
  93. 93. Wang C, Zhao G, Wang S, Chen Y, Gong Y, Chen S, et al. A simplified derivative of human defensin 5 with potent and efficient activity against multidrug-resistant Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy. 2018;62(2):e01504-e01517
  94. 94. Kaushal A, Gupta K, van Hoek ML. Characterization of Cimex lectularius (bedbug) defensin peptide and its antimicrobial activity against human skin microflora. Biochemical and Biophysical Research Communications. 2016;470(4):955-960
  95. 95. Routsias JG, Karagounis P, Parvulesku G, Legakis NJ, Tsakris A. In vitro bactericidal activity of human β-defensin 2 against nosocomial strains. Peptides. 2010;31(9):1654-1660
  96. 96. Maisetta G, Batoni G, Esin S, Florio W, Bottai D, Favilli F, et al. In vitro bactericidal activity of human beta-defensin 3 against multidrug-resistant nosocomial strains. Antimicrobial Agents and Chemotherapy. 2006;50(2):806-809
  97. 97. Kim MK, Kang N, Ko SJ, Park J, Park E, Shin DW, et al. Antibacterial and antibiofilm activity and mode of action of magainin 2 against drug-resistant Acinetobacter baumannii. International Journal of Molecular Sciences. 2018;19(10):3041
  98. 98. Zasloff M. Magainins a class of antimicrobial peptides from Xenopus skin: Isolation characterization of two active forms and partial cDNA sequence of a precursor. Proc Natl Acad Sci USA. 1987;84(15):5449-5453
  99. 99. Flamm RK, Rhomberg PR, Simpson KM, Farrell DJ, Sader HS, Jones RN. In vitro spectrum of pexiganan activity when tested against pathogens from diabetic oot infections and with selected resistance mechanisms. Antimicrobial Agents and Chemotherapy. 2015;59(3):1751-1754
  100. 100. Ge Y MacDonald, DL Holroyd, KJ Thornsberry C, Wexler H, Zasloff M. In vitro antibacterial properties of pexiganan an analog of magainin. Antimicrobial Agents and Chemotherapy 1999; 43(4):782-788
  101. 101. Jáskiewicz M, Neubauer D, Kazor K, Bartoszewska S, Kamysz W. Antimicrobial activity of selected antimicrobial peptides against planktonic culture and biofilm of Acinetobacter baumannii. Probiotics Antimicrob Proteins. 2019;11(1):317-324
  102. 102. Conlon JM, Ahmed E, Condamine E. Antimicrobial properties of brevinin-2-related peptide and its analogs: Efficacy against multidrug-resistant Acinetobacter baumannii. Chemical Biology & Drug Design. 2009;74(5):488-493
  103. 103. Conlon JM, Sonnevend A, Pál T, Vila-Farrés X. Efficacy of six frog skin-derived antimicrobial peptides against colistin-resistant strains of the Acinetobacter baumannii group. International Journal of Antimicrobial Agents. 2012;39(4):317-320
  104. 104. Liu CB, Shan B, Bai HM, Tang J, Yan LZ, Ma YB. Hydrophilic/hydrophobic characters of antimicrobial peptides derived from animals and their effects on multidrug-resistant clinical isolates. Dongwuxue Yanjiu = Zool Res. 2015;36(1):41-47
  105. 105. Al-Ghaferi N, Kolodziejek J, Nowotny N, Coquet L, Jouenne T, Leprince J, et al. Antimicrobial peptides from the skin secretions of the southeast Asian frog Hylarana erythraea (Ranidae). Peptides. 2010;31(4):548-554
  106. 106. Conlon JM, Ahmed E, Pal T. A Sonnevend potent and rapid bactericidal action of alyteserin-1c and its [E4K] analog against multidrug-resistant strains of Acinetobacter baumannii. Peptides. 2010;31(10):1806-1810
  107. 107. Conlon JM, Mechkarska M, Arafat K, Attoub S, Sonnevend A. Analogues of the frog skin peptide alyteserin-2a with enhanced antimicrobial activities against gram-negative bactéria. Journal of Peptide Science. 2012;18(4):270-275
  108. 108. McLean DTF, McCrudden MTC, Linden GJ, Irwin CR, Conlon JM, Lundy FT. Antimicrobial and immunomodulatory properties of PGLa-AM1 CPFAM1 and magainin-AM1: Potent activity against oral pathogens. Regulatory Peptides. 2014;194-195:63-68
  109. 109. Conlon JM, Al-Ghaferi N, Ahmed E, Meetani MA, Leprince JJ, Nielsen PF. Orthologs of magainin PGLa procaerulein-derived and proxenopsin-derived peptides from skin secretions of the octoploid frog Xenopus amieti (Pipidae). Peptides. 2010;31(6):989-994
  110. 110. Conlon JM, Mechkarska M, Ahmed E, Leprince J, Vaudry H, King JD, et al. Purification and properties of antimicrobial peptides from skin secretions of the Eritrea clawed frog Xenopus clivii (Pipidae). Comp Biochem Physiol C Toxicol Pharmacol. 2011;153(3):350-354
  111. 111. Mechkarska M, Ahmed E, Coquet L, Leprince J, Jouenne T, Vaudry H, et al. Antimicrobial peptides with therapeutic potential from skin secretions of the Marsabit clawed frog Xenopus borealis (Pipidae). Comp Biochem Physiol C Toxicol Pharmacol. 2010;152(4):467-472
  112. 112. Mechkarska M, Prajeep M, Radosavljevic GD, Jovanovic IP, Al Baloushi A, Sonnevend A, et al. An analog of the host-defense peptide hymenochirin-1B with potent broad-spectrum activity against multidrug-resistant bacteria and immunomodulatory properties. Peptides. 2013;50:153-159
  113. 113. Serra I, Scorciapino MA, Manzo G, Casu M, Rinaldi AC, Attoub S, et al. Conformational analysis and cytotoxic activities of the frog skin host-defense peptide hymenochirin-1Pa. Peptides. 2014;61:114-121
  114. 114. Conlon JM, Galadari S, Raza H, Condamine E. Design of potent non-toxic antimicrobial agents based upon the naturally occurring frog skin peptides ascaphin-8 and peptide XT-7. Chemical Biology & Drug Design. 2008;72(1):58-64
  115. 115. Park CB, Kim HS, Kim SC. Mechanism of action of the antimicrobial peptide buforin II: Buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochemical and Biophysical Research Communications. 1998;244(1):253-257
  116. 116. Cirioni O, Silvestri C, Ghiselli R, Orlando F, Riva A, Gabrielli E, et al. Therapeutic efficacy of buforin II and rifampin in a rat model of Acinetobacter baumannii sepsis. Critical Care Medicine. 2009;37(4):1403-1407
  117. 117. Pashaei F, Bevalian P, Akbari R, Bagheri KP. Single-dose eradication of extensively drug-resistant Acinetobacter spp. in a mouse model of burn infection by melittin antimicrobial peptide. Microbial Pathogenesis. 2019;127:60-69
  118. 118. Akbari R, Hakemi-Vala M, Pashaie F, Bevalian P, Hashemi A, Bagheri KP. Highly synergistic effects of melittin with conventional antibiotics against multidrug-resistant isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Microbial Drug Resistance. 2019;25(2):193-202
  119. 119. Giacometti A, Cirioni O, Kamysz W, D’Amato G, Silvestri C, Del Prete MS, et al. Comparative activities of cecropin a melittin and cecropin A-melittin peptide CA(1-7)M(2-9)NH2 against multidrug-resistant nosocomial isolates of Acinetobacter baumannii. Peptides. 2003;24(9):1315-1318
  120. 120. Jayamani E, Rajamuthiah R, Larkins-Ford J, Fuchs BB, Conery AL, Vilcinskas A, et al. Insect-derived cecropins display activity against Acinetobacter baumannii in a whole-animal high-throughput Caenorhabditis elegans model. Antimicrobial Agents and Chemotherapy. 2015;59(3):1728-1737
  121. 121. Gui S, Li R, Feng Y, Wang S. Transmission electron microscopic morphological study and flow cytometric viability assessment of Acinetobacter baumannii susceptible to Musca domestica cecropin. Scientific World Journal. 2014;2014:657536
  122. 122. Boman HG, Agerberth B, Boman A. Mechanisms of action on Escherichia coli of cecropin P1 and PR-39 two antibacterial peptides from pig intestine. Infection and Immunity. 1993;61(7):2978-2984
  123. 123. Peng J, Long H, Liu W, Wu Z, Wang T, Zeng Z, et al. Antibacterial mechanism of peptide cec4 against Acinetobacter baumannii. Infect Drug Resist. 2019;12:2417-2428
  124. 124. Han HM, Ko S, Cheong M-J, Bang JK, Seo CH, Luchian T, et al. Myxinidin2 and myxinidin3 suppress inflammatory responses through STAT3 and MAPKs to promote wound healing. Oncotarget. 2017;8(50):87582-87597
  125. 125. Gordya N, Yakovlev A, Kruglikova A, Tulin D, Potolitsina E, Suborova T, et al. Natural antimicrobial peptide complexes in the fighting of antibiotic-resistant biofilms: Calliphora vicina medicinal maggots. PLoS One. 2017;12(3):e0173559
  126. 126. Vila-Farrés X, López-Rojas R, Pachón-Ibáñez ME, Teixidó M, Pachón J, Vila J, et al. Sequence-activity relationship and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii. European Journal of Medicinal Chemistry. 2015;101:34-40
  127. 127. Al-Khafaji Z, Al-Samaree M. Design of synthetic antimicrobial peptides against resistant Acinetobacter baumannii using computational approach. Int J Pharmaceut Sci Res. 2017;8:2033-2039255
  128. 128. Lin CH, Lee MC, Tzen JTC, Lee HM, Chang SM, Tu WC, et al. Efficacy of mastoparan-AF alone and in combination with clinically used antibiotics on nosocomial multidrug-resistant Acinetobacter baumannii Saudi. Journal of Biological Sciences. 2017;24(5):1023-1029
  129. 129. Tartar AS, Balın SO, Akbulut A, Yardım M, Aydın S. Roles of Dermcidin Salusin-α Salusin-β and TNF-α in the pathogenesis of human brucellosis. Iranian Journal of Immunology. 2019;16(2):182-189
  130. 130. Farshadzadeh Z, Modaresi MH, Taheri B, Rahimi S, Bahador A. InVitro antimicrobial activity of dermcidin-1L against extensively-drug-resistant and pandrug resistant Acinetobacter baumannii. Jundishapur J Microbiol. 2017;10(5):e13201
  131. 131. Mohamed MF, Hamed MI, Panitch A, Seleem MN. Targeting methicillin-resistant Staphylococcus aureus with short salt-resistant synthetic peptides. Antimicrobial Agents and Chemotherapy. 2014;58(7):4113-4122
  132. 132. Mohamed MF, Brezden A, Mohammad H, Chmielewski J, Seleem MN. A short D-enantiomeric antimicrobial peptide with potent immunomodulatory and antibiofilm activity against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Scientific Reports. 2017;7(1):6953
  133. 133. Wu X, Li Z, Li X, Tian Y, Fan Y, Yu C, et al. Synergistic effects of antimicrobial peptide DP7 combined with antibiotics against multidrug-resistant bacteria. Drug Des Dev Ther. 2017;11:939-946
  134. 134. Zhang R, Wang Z, Tian Y, Yin Q, Cheng X, Lian M, et al. Efficacy of antimicrobial peptide DP7 designed by machine-learning method against methicillin-resistant Staphylococcus aureus. Frontiers in Microbiology. 2019;10:1175
  135. 135. Nagarajan D, Roy N, Kulkarni O, Nanajkar N, Datey A, Ravichandran S, et al. Ω76: A designed antimicrobial peptide to combat carbapenem- and tigecycline resistant Acinetobacter baumannii. Science Advances. 2019;5(7):eaax1946
  136. 136. Mourtada R, Herce HD, Yin DJ, Moroco JÁ, Wales TE, Engen JR, et al. Design of stapled antimicrobial peptides that are stable, nontoxic, and kill antibiotic-resistant bacteria in mice. Nature Biotechnology. 2019;37(10):1186-1197
  137. 137. Rose M, Lapuebla A, Landman D, Quale J. In vitro and in vivo activity of a novel antisense peptide nucleic acid compound against multidrug-resistant Acinetobacter baumannii. Microbial Drug Resistance. 2019;25(7):961-965
  138. 138. Gopal R, Kim YG, Lee JH, Lee SK, Chae JD, Son BK, et al. Synergistic effects and antibiofilm properties of chimeric peptides against multidrug-resistant Acinetobacter baumannii strains. Antimicrobial Agents and Chemotherapy. 2014;58(3):1622-1629
  139. 139. Hong MJ, Kim MK, Park Y. Comparative antimicrobial activity of Hp404 peptide and its analogs against Acinetobacter baumannii. International Journal of Molecular Sciences. 2021;22(11):5540
  140. 140. Neshani A, Sedighian H, Mirhosseini SA, Ghazvini K, Zare H, Jahangiri A. Antimicrobial peptides as a promising treatment option against Acinetobacter baumannii infections. Microbial Pathogenesis. 2020;146:104238
  141. 141. Jayathilaka EHTT, Rajapaksha DC, Nikapitiya C, De Zoysa M, Whang I. Antimicrobial and anti-biofilm peptide octominin for controlling multidrug-resistant Acinetobacter baumannii. International Journal of Molecular Sciences. 2021;22(10):5353
  142. 142. Hacioglu M, Oyardi O, Bozkurt-Guzel C, Savage PB. Antibiofilm activities of ceragenins and antimicrobial peptides against fungal-bacterial mono and multispecies biofilms. Journal of Antibiotics (Tokyo). 2020;73(7):455-462
  143. 143. Morroni G, Simonetti O, Brenciani A, Brescini L, Kamysz W, Kamysz E, et al. In vitro activity of protegrin-1 alone and in combination with clinically useful antibiotics against Acinetobacter baumannii strains isolated from surgical wounds. Medical Microbiology and Immunology. 2019;208(6):877-883
  144. 144. Sharma D, Choudhary M, Vashistt J, Shrivastava R, SinghBisht G. Cationic antimicrobial peptide and its poly-N-substituted glycine congener: Antibacterial and antibiofilm potential against a baumannii. Biochemical and Biophysical Research Communications. 2019;518(3):472-478
  145. 145. Mohan NM, Zorgani A, Jalowicki G, Kerr A, Khaldi N, Martins M. Unlocking nuripep 1653 from common pea protein: A potent antimicrobial peptide to tackle a pan-drug resistant Acinetobacter baumannii. Frontiers in Microbiology. 2019;10:2086
  146. 146. Dowzinkly MJ, Chmelarová E. Antimicrobial susceptibility of gram-negative and gram-positive bacteria collected from Eastern Europe: Results from the Tigecycline evaluation and surveillance trial (T.E.S>T.), 2011-2016. J. Glob. Antimicrobial Resist. 2019;17(44):44-52. DOI: 10.1016/j.jgar.2018.11.007
  147. 147. Björstad Å, Askarieh G, Brown KL, Christenson K, Forsman H, Önnheim K, et al. The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes. Antimicrob Ag Chemother. 2009;53(3):1027-1038. DOI: 10.1128/AAC.01310-08
  148. 148. De Y, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, et al. LL-37 the neutrophil granule-and epithelial cell-derived cathelicidin utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils monocytes and T cells. The Journal of Experimental Medicine. 2000;192(7):1069-1074. DOI: 10.1084/jem.192.7.1069
  149. 149. Nijnik A, Hancock REW. Host defense peptides: Antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections. Emerg.Health Threats J. 2009;2:e1. DOI: 10.3134/ehtj.09.001
  150. 150. Neshani A, Zare H, Eidgahi MRA, Kakhki RK, Safdari H, Khaledi A, et al. LL-37: A review of antimicrobial profile against sensitive and antibiotic-resistant human bacterial pathogens. Gene Rep. 2019;17:100519. DOI: 10.1016/j.genrep.2019.100519
  151. 151. Esfandiyari R, Halabian R, Behzadi E, Sedighian H, Jafari R, Fooladi AAI. Performance evaluation of antimicrobial peptide ll-37 and hepcidin and β-defensin-2 secreted by mesenchymal stem cells. Heliyon. 2019;5(10):e02652. DOI: 10.1016/j.heliyon.2019.e02652
  152. 152. Liu C, Shan B, Qi J, Ma Y. Systemic responses of multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii following exposure to the antimicrobial peptide cathelicidin-BF imply multiple intracellular targets. Frontiers in Cellular and Infection Microbiology. 2017;7:466. DOI: 10.3389/fcimb.2017.00466
  153. 153. Zhao H, Gan TX, Liu XD, Jin Y, Lee WH, Shen JH, et al. Identification and characterization of novel reptile cathelicidins from elapid snakes. Peptides. 2008;29(10):1685-1691. DOI: 10.1016/j.peptides.2008.06.008
  154. 154. Du H, Samuel RL, Massiah MA, Gillmor SD. The structure and behavior of the NA-CATH antimicrobial peptide with liposomes. Biochimica et Biophysica Acta. 2015;1848(10 Pt A):2394-2405. DOI: 10.1016/j.bbamem.2015.07.006
  155. 155. Ikenaga M, Guevara R, Dean AL, Pisani C, Boyer JN. Changes in community structure of sediment bacteria along the Florida coastal everglades marsh-mangrove-seagrass salinity gradient. Microbial Ecology. 2010;59(2):284-295. DOI: 10.1007/s00248-009-9572-2
  156. 156. Bishop BM, Juba ML, Devine MC, Barksdale SM, Rodriguez CA, Chung MC, et al. Bioprospecting the American alligator (Alligator mississippiensis) host defense peptidome. PLoS One. 2015;10(2):e0117394. DOI: 10.1371/journal.pone.0117394
  157. 157. Daly KA, Digby MR, Lefévre C, Nicholas KR, Deane EM, Williamson P. Identification characterization and expression of cathelicidin in the pouch young of Tammar wallaby (Macropus eugenii). Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 2008;149(3):524-533. DOI: 10.1016/j.cbpb.2007.12.002
  158. 158. Selsted ME, Novotny MJ, Morris WL, Tang YQ, Smith W, Cullor JS. Indolicidin is a novel bactericidal tridecapeptide amide from neutrophils. The Journal of Biological Chemistry. 1992;267(7):4292-4295
  159. 159. Végh AG, Nagy K, Bálint Z, Kerényi A, Rákhely G, Váró G, et al. Effect of antimicrobial peptide-amide: Indolicidin on biological membranes. Journal of Biomedicine & Biotechnology. 2011;2011:670589. DOI: 10.1155/2011/670589
  160. 160. Hsu CH, Chen C, Jou ML, Lee AYL, Lin YC, Yu YP, et al. Structural and DNA-binding studies on the bovine antimicrobial peptide indolicidin: Evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Research. 2005;33(13):4053-4064. DOI: 10.1093/nar/gki725
  161. 161. Marchand C, Krajewski K, Lee HF, Antony S, Johnson AA, Amin R, et al. Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites. Nucleic Acids Research. 2006;34(18):5157-5165. DOI: 10.1093/nar/gkl667
  162. 162. Schneider JJ, Unholzer A, Schaller M, Schäfer-Korting M, Korting HC. Human defensins, Journal of Molecular Medicine (Berlin, Germany). 2005;83(8):587-595. DOI: 10.1007/s00109-005-0657-1
  163. 163. Knutelski S, Awad M, Łukasz N, Bukowski M, Śmiałek J, Suder P, et al. Isolation, identification, and bioinformatic analysis of antibacterial proteins and peptides from immunized hemolymph of red palm weevil Rhynchophorus ferrugineus. Biomolecules. 2021;11(1):83. DOI: 10.3390/ iom11010083
  164. 164. Lehrer RI, Lu W. α-Defensins in human innate immunity. Immunological Reviews. 2012;45(1):84-112. DOI: 10.1111/j.1600-065X.2011.01082.x
  165. 165. Wang C, Zhao G, Wang S, Chen Y, Gong Y, Chen S, et al. A simplified derivative of human defensin 5 with potent and efficient activity against multidrug-resistant Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy. 2018;62(2):e01504-e01517. DOI: 10.1128/AAC.01504-17
  166. 166. Wanniarachchi YA, Kaczmarek P, Wan A, Nolan EM. Human defensin 5 disulfide array mutants: Disulfide bond deletion attenuates antibacterial activity against Staphylococcus aureus. Biochemistry. 2011;37:8005-8017. DOI: 10.1021/bi201043j
  167. 167. Marcelino-Pérez G, Ruiz-Medrano R, Gallardo-Hernández S, Xoconostle-Cázares B. Adsorption of recombinant human β-defensin 2 and two mutants on mesoporous silica nanoparticles and its effect against Clavibacter michiganensis subsp. Michiganensis. Nanomaterials (Basel). 2021;11(8):2144. DOI: 10.3390/nano11082144
  168. 168. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, et al. Human beta defensin-3 promotes wound healing in infected diabetic wounds. The Journal of Gene Medicine. 2009;11(3):220-228. DOI: 10.1002/jgm.1287
  169. 169. Zerweck J, Strandberg E, Kukharenko O, Reichert J, Bürck J, Wadhwani P, et al. Molecular mechanism of synergy between the antimicrobial peptides PGLa and magainin 2. Scientific Reports. 2017;7:13153. DOI: 10.1038/s41598-017-12599-7
  170. 170. Tamba Y, Yamazaki M. Magainin 2-induced pore formation in the lipid membranes depends on its concentration in the membrane interface. The Journal of Physical Chemistry. B. 2009;113(14):4846-4852. DOI: 10.1021/jp8109622
  171. 171. Maloy WL, Kari UP. Structure-activity studies on magainins and other host defense peptides. Biopolymers. 1995;37(2):105-122. DOI: 10.1002/bip.360370206
  172. 172. Gottler LM, Ramamoorthy A. Structure membrane orientation mechanism and function of pexiganan-a highly potent antimicrobial peptide designed from magainin. Biochimica et Biophysica Acta. 2009;1788(8):1680-1686
  173. 173. Ramamoorthy A, Thennarasu S, Lee DK, Tan A, Maloy L. Solid-state NMR investigation of the membrane-disrupting mechanism of antimicrobial peptides MSI-78 and MSI-594 derived from magainin 2 and melittin. Biophysical Journal. 2006;91(1):206-216. DOI: 10.1529/biophysj.105.07 3890
  174. 174. Fuchs PC, Barry AL, Brown SD. In vitro antimicrobial activity of MSI-78 a magainin analog. Antimicrobial Agents and Chemotherapy. 1998;42(5):1213-1216. DOI: 10.1128/AAC. 42.5.1213
  175. 175. Bevier CR, Sonnevend A, Kolodziejek J, Nowotny N, Nielsen PF, Conlon JM. Purification and characterization of antimicrobial peptides from the skin secretions of the mink frog (Rana septentrionalis). Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 2004;139(1–3):31-38. DOI: 10.1016/j.cca.2004.08.019
  176. 176. Conlon JM, Abraham B, Sonnevend A, Jouenne T, Cosette P, Leprince J, et al. Purification and characterization of antimicrobial peptides from the skin secretions of the carpenter frog Rana virgatipes (Ranidae, Aquarana). Regulatory Peptides. 2005;131(1–3):38-45. DOI: 10.1016/j.regpep.20 05.06.003
  177. 177. Savelyeva A, Ghavami S, Davoodpour P, Asoodeh A, Los MJ. An overview of Brevinin superfamily: Structure function and clinical perspectives. Advances in Experimental Medicine and Biology. 2014;818:197-212. DOI: 10.1007/978-1-4471-6458-610
  178. 178. Popovic S, Urbán E, Lukic M, Conlon JM. Peptides with antimicrobial and anti-inflammatory activities that have therapeutic potential for treatment of acne vulgaris. Peptides. 2012;34(2):275-282. DOI: 10.1016/j.peptides.2012.02.010
  179. 179. Popovic S, Djurdjevic P, Zaric M, Mijailovic Z, Avramovic D, Baskic D. Effects of host defense peptides B2RP Brevinin-2GU D-Lys-Temporin Lys-XT-7 and DLys-Ascaphin-8 on peripheral blood mononuclear cells: Preliminary study. Periodicum Biologorum. 2017;119(2):113-118. DOI: 10.18054/pb.v119i2.4781
  180. 180. Conlon JM, Demandt A, Nielsen PF, Leprince J, Vaudry H, Woodhams DC. The alyteserins: Two families of antimicrobial peptides from the skin secretions of the midwife toad Alytes obstetricans (Alytidae). Peptides. 2009;30(6):1069-1073. DOI: 10.1016/j.peptides.2009.03.004
  181. 181. Subasinghage AP, O'Flynn D, Conlon JM, Hewage CM. Conformational and membrane interaction studies of the antimicrobial peptide alyteserin-1c and its analog [E4K] alyteserin-1c. Biochimica et Biophysica Acta. 2011;1808(8):1975-1984. DOI: 10.1016 /j.bbamem.2011.04.012
  182. 182. Conlon JM, Prajeep M, Mechkarska M, Coquet L, Leprince J, Jouenne T, et al. Characterization of the host-defense peptides from skin secretions of Merlin's clawed frog Pseudhymenochirus Merlini: Insights into phylogenetic relationships among the Pipidae. Comp. Biochem. Physiol. Part D Genom. Proteonomics. 2013;8(4):352-357. DOI: 10.1016/j.cbd.2013.10.002
  183. 183. Ali MF, Soto A, Knoop FC, Conlon JM. Antimicrobial peptides isolated from skin secretions of the diploid frog Xenopus tropicalis (Pipidae). Biochimica et Biophysica Acta. 2001;1550(1):81-89. DOI: 10.1016/s0167-4838 (01)00272-2
  184. 184. Park CB, Kim MS, Kim SC. A novel antimicrobial peptide from Bufo bufo gargarizans. Biochemical and Biophysical Research Communications. 1996;218(1):408-413. DOI: 10. 1006/bbrc.1996.0071
  185. 185. Fennell JF, Shipman WH, Cole LJ. Antibacterial action of melittin, a polypeptide from bee venom. Proceedings of the Society for Experimental Biology and Medicine. 1968;127(3):707-710. DOI: 10.3181/ 00379727-127-32779
  186. 186. Park J, Kwon O, An HJ, Park KK. Antifungal effects of bee venom components on Trichophyton rubrum: A novel approach of bee venom study for possible emerging antifungal agent. Annals of Dermatology. 2018;30(2):202-210. DOI: 10.5021/ ad.2018.30.2. 202
  187. 187. Pereira AV, de Barros G, Pinto EG, Tempone AG, Orsi RO, Dos Santos LD, et al. Melittin induces in vitro death of Leishmania (Leishmania) infantum by triggering the cellular innate immune response. Journal of Venomous Animals and Toxins including Tropical Diseases. 2016;22:1. DOI: 10.1186/s40409-016-0055-x
  188. 188. Kim YW, Chaturvedi PK, Chun SN, Lee YG, Ahn WS. Honeybee venom possesses anticancer and antiviral effects by differential inhibition of HPV E6 and E7 expression on cervical cancer cell line. Oncology Reports. 2015;33(4):1675-1682. DOI: 10.3892/or. 2015.3760
  189. 189. Van den Bogaart G, Guzman JV, Mika JT, Poolman B. On the mechanism of pore formation by melittin. The Journal of Biological Chemistry. 2008;283(49):33854-33857. DOI: 10.1074/jbc.M805171200
  190. 190. Rangel K, Lechuga GC, Almeida Souza AL, Carvalho JPRS, Villas-Bôas MHS, De Simone SG. Pan-drug resistant Acinetobacter baumannii but not other strains are resistant to the bee venom peptide melittin. Antibiotics (Basel). 2020;149(4):178. DOI: 10.3390/antibiotics9040178
  191. 191. Steiner H, Hultmark D, Engström Å, Bennich H, Boman HG. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature. 1981;292(5820):246. DOI: 10.1038/292246a0
  192. 192. Hui L, Leung K, Chen HM. The combined effects of antibacterial peptide cecropin a and anticancer agents on leukemia cells. Anticancer Research. 2002;22(5):2811-2816
  193. 193. Wu Q, Patočka J, Kuča K. Insect Antimicrobial Peptides, a Mini Review. Toxins (Basel). 2018;10(11):461. DOI: 10.3390/toxins10110461
  194. 194. Yun J, Lee DG. Cecropin A-induced apoptosis is regulated by ion balance and glutathione antioxidant system in Candida albicans. IUBMB Life. 2016;68(8):652-662. DOI: 10.1002/iub.1527
  195. 195. Hirai Y, Yasuhara T, Yoshida H, Nakajima T, Fujino M, Kitada C. A new mast cell degranulating peptide “mastoparan” in the venom of Vespula lewisii. Chem Pharm Bull (Tokyo). 1979;27(8):1942-1944. DOI: 10.1248/cpb.27.1942
  196. 196. Moreno M, Giralt E. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: Melittin apamin and mastoparan. Toxins. 2015;7(4):1126-1150. DOI: 10.3390/toxins7041126
  197. 197. Chen X, Zhang L, Wu Y, Wang L, Ma C, Xi X, et al. Evaluation of the bioactivity of a mastoparan peptide from wasp venom and of its analogues designed through targeted engineering. International Journal of Biological Sciences. 2018;14(6):599-607. DOI: 10.7150/ijbs.234 19
  198. 198. Sun H, Hong Y, Xi Y, Zou Y, Gao J, Du J. Synthesis self-assembly and biomedical applications of antimicrobial peptide-polymer conjugates. Biomacromolecules. 2018;19(6):1701-1720. DOI: 10.1021/acs.biomac.8b00 208
  199. 199. Oppenheim FG, Xu T, McMillian FM, Levitz SM, Diamond RD, Offner GD, et al. Histatins a novel family of histidine-rich proteins in human parotid secretion isolation characterization primary structure and fungistatic effects on Candida albicans. The Journal of Biological Chemistry. 1988;263(16):7472-7477
  200. 200. Murakami Y, Tamagawa H, Shizukuishi S, Tsunemitsu A, Aimoto S. Biological role of an arginine residue present in a histidine-rich peptide which inhibits hemagglutination of Porphyromonas gingivalis. FEMS Microbiology Letters. 1992;77(1–3):201-204. DOI: 10.1016/0378-1097(92)90156-i
  201. 201. Burian M, Schittek B. The secrets of dermcidin action. International Journal of Medical Microbiology. 2015;305(2):283-286. DOI: 10.1016/j.ijmm.2014.12.012
  202. 202. Muta T, Fujimoto T, Nakajima H, Iwanaga S. Tachyplesins isolated from hemocyte of southeast Asian horseshoe crabs (Carcinoscorpius rotundicauda and Tachypleus gigas): Identification of a new tachyplesin tachyplesin III and a processing intermediate of its precursor. Journal of Biochemistry. 1990;108(9):261-266. DOI: 10.1093/oxfordjournals. jbchem.a123191
  203. 203. Liu C, Qi J, Shan B, Ma Y. Tachyplesin causes membrane instability that kills multidrug-resistant bacteria by inhibiting the 3-ketoacyl carrier protein reductase FabG. Frontiers in Microbiology. 2018;9:825. DOI: 10.3389/fmicb.2018.00825
  204. 204. Rahbar MR, Zarei M, Jahangiri A, Khalili S, Nezafat N, Negahdaripour M, et al. Pierce into the native structure of Ata, a trimeric autotransporter of Acinetobacter baumannii ATCC 17978. Int. J. Pept. Res. Therapeut. 2020;26:1269-1282
  205. 205. Jahangiri A, Rasooli I, Owlia P, Fooladi AAI, Salimian J. An integrative in silico approach to the structure of Omp33-36 in Acinetobacter baumannii. Computational Biology and Chemistry. 2018;72:77-86. DOI: 10.1016/j.compbiolchem.2018.01.003
  206. 206. Rasooli I, Abdolhamidi R, Jahangiri A, Astaneh DAS. Outer membrane protein Oma87 prevents Acinetobacter baumannii infection. International Journal of Peptide Research and Therapeutics. 2020;9:1-8. DOI: 10.1007/s10989-020-10056-0
  207. 207. Rahbar MR, Zarei M, Jahangiri A, Khalili S, Nezafat N, Negahdaripour M, et al. Trimeric autotransporter adhesins in Acinetobacter baumannii coincidental evolution at work. Infection, Genetics and Evolution. 2019;71:116-127. DOI: 10.1016/j. meegid.2019.03.023
  208. 208. Nagarajan D, Nagarajan T, Roy N, Kulkarni O, Ravichandran S, Mishra M, et al. The Journal of Biological Chemistry. 2018;293(10):3492-3509. DOI: 10.1074/jbc.M117.805499
  209. 209. Misawa T, Goto C, Shibata N, Hirano M, Kikuchi Y, Naito M, et al. Rational design of novel amphipathic antimicrobial peptides focused on the distribution of cationic amino acid residues. Med. Chem. Comm. 2019;10(6):896-900. DOI: 10.1039/c9md0 0166b
  210. 210. Khan MTH. Recent Trends on QSAR in the Pharmaceutical Perceptions. Sharjah, United Arab Emirates: Bentham Science Publishers; 2012. ISBN: 978-1-60805-433-6
  211. 211. Wu X, Wang Z, Li X, Fan Y, He G, Wan Y, et al. In vitro and in vivo activities of antimicrobial peptides developed using an amino acid-based activity prediction method. Antimicrobial Agents and Chemotherapy. 2014;58(9):5342-5349
  212. 212. Ageitos JM, Sánchez-Pérez A, Calo-Mata P, Villa TG. Antimicrobial peptides (AMPs): Ancient compounds that represent novel weapons in the fight against bacteria. Biochemical Pharmacology. 2017;133:117. DOI: 10.1016/j.bcp.2016.09.018
  213. 213. Andersson DI, Hughes D, Kubicek-Sutherland JZ. Mechanisms and consequences of bacterial resistance to antimicrobial peptides. Drug Resistance Updates. 2016;26:43-57. DOI: 10.1016/j.drup. 2016.04.002
  214. 214. Moravej H, Moravej Z, Yazdanparast M, Heiat M, Mirhosseini A, Moghaddam MM, et al. Antimicrobial peptides: Features action and their resistance mechanisms in bacteria. Microbial Drug Resistance. 2018;24(6):747. DOI: 10.1089/mdr.2017.0392
  215. 215. Joo HS, Fu CI, Otto M. Bacterial strategies of resistance to antimicrobial peptides. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 2016;371(1695):20150292. DOI: 10.1098/rstb. 2015.0292
  216. 216. Omardien S, Brul S, Zaat SAJ. Antimicrobial activity of cationic antimicrobial peptides against gram-positive: Current progress made in understanding the mode of action and the response of bacteria. Front. Cell. Develop. Biol. 2016;4:111. DOI: 10.3389/fcell.2016.00111
  217. 217. Jeannot K, Bolard A, Plésiat P. Resistance to polymyxins in gram-negative organisms. Int. J. Antimicr Ag. 2017;49(5):526-535. DOI: 10.1016/j.ijantimicag.2016. 11.029
  218. 218. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study. The Lancet Infectious Diseases. 2016;16(2):161-168. DOI: 10.1016/S1473-3099(15)00424-7
  219. 219. Paterson DL, Harris PNA. Colistin resistance: A major breach in our last line of defense. The Lancet Infectious Diseases. 2016;16(2):132-133. DOI: 10.1016/S1473-3099(15)00463-6
  220. 220. Macnair CR, Stokes JM, Carfrae LA, Fiebig-Comyn AA, Coombes BK, Mulvey MR, et al. Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. Nature Communications. 2018;9(1):458. DOI: 10.1038/s41467-018-02875-z
  221. 221. Morita Y, Tomida J, Kawamura Y. MexXY multidrug efflux system of Pseudomonas aeruginosa. Frontiers in Microbiology. 2012;3:408. DOI: 10.3389/fmicb.2012.00408
  222. 222. Bechinger B, Gorr SU. Antimicrobial peptides: Mechanisms of action and resistance. Journal of Dental Research. 2017;96(3):254-260. DOI: 10.1177/0022034516679973
  223. 223. Gheorghe I, Saviuc C, Ciubuca B, Lazar V, Chifiriuc MC. Chapter 8—Nano drug delivery. In: Grumezescu AM, editor. Nanomaterials for Drug Delivery and Therapy. Norwich NY USA: William Andrew Publishing; 2019. pp. 225-244. ISBN: 978-0-12-816505-8
  224. 224. Sun B, Wibowo D, Middelberg APJ, Zhao CX. Cost-effective downstream processing of recombinantly produced pexiganan peptide and its antimicrobial activity. AMB Express. 2018;8(1):1-14. DOI: 10.1186/s13568-018-0541-3
  225. 225. Brannon JR, Burk DL, Leclerc JM, Thomassin JL, Portt A, Berghuis AM, et al. Inhibition of outer membrane proteases of the omptin family by aprotinin. Infection and Immunity. 2015;83(6):2300-2311. DOI: 10.1128/IAI.00136-15

Written By

Karyne Rangel and Salvatore Giovanni De-Simone

Submitted: 23 July 2021 Reviewed: 09 September 2021 Published: 16 April 2022