Ribosomally synthesized antimicrobial peptides (AMPs) constitute a structurally diverse group of molecules found virtually in all organisms. Most antimicrobial peptides contain less than 100 amino acid residues, have a net positive charge, and are membrane active. They are major players in the innate immune defense but can also have roles in processes as chemokine induction, chemotaxis, inflammation, and wound healing. In addition to their antimicrobial effects, many of them show antiviral and antineoplastic activities.
AMPs are a heterogeneous group of relatively small molecules usually containing less than a hundred amino acids. They were first described in the 1960’s by Zeya and Spitznagel in polymorphonuclear leukocyte lysosomes.
To date, more than 2600 AMPs have been identified and registered in databases. They are produced by nearly all groups of organisms, including bacteria, fungi, plants, and animals. Many vertebrate AMPs are secreted by epithelial surfaces such as the tracheal, lingual, or intestinal mucosa of mammals or the skin of amphibia. Some are expressed in neutrophils, monocytes, and macrophages.
AMPs are involved in both animal and plant immune defense systems. Constitutively expressed or induced they play a key role in the first line of defense against microbial intruders.
AMPs can be classified on the basis of their amino acid composition and structure. Two major groups of AMPs can be distinguished. The first group consists of linear molecules which either tend to adopt α-helical structure or are enriched in certain amino acids such as arginine, glycine, histidine, proline, and tryptophan. The second group consists of cysteine-containing peptides which can be divided into single or multiple disulfide structures. In many cases, the presence of disulfide bridges is required for antimicrobial activity.
Most AMPs are cationic peptides, but there are also anionic peptides such as dermcidin, an aspartic acid-rich peptide from human and maximin H5 from amphibian skin. Other non-cationic AMPs include fragments from neuropeptide precursor molecules such as proenkephalin A, aromatic dipeptides primarily isolated from dipteran larvae, or peptides derived from oxygen-binding proteins from arthropod or annelid species.
Mode of Action
Most AMPs act by provoking an increase in plasma membrane permeability. They preferentially target microbial versus mammalian cells. Selectivity is influenced by several factors such as differences in membrane composition: membranes of many bacterial pathogens contain negatively charged lipid moieties such as phosphatidylglycerol (PG), cardiolipin, and phosphatidylserine (PS), whereas mammalian membranes, commonly enriched in phosphatidylethanolamine (PE), phosphatidylcholine (PC) and sphingomyelin, are generally neutral in net charge.
The presence of sterols such as cholesterol and ergesterol within the membrane may be a further means by which AMPs can distinguish between mammalian or fungal cells and prokaryotes. A first step in the mechanism of membrane permeabilization is the electrostatic interaction between the positively charged AMP with the negatively charged membrane surface of the microorganism. Subsequent disruption of the membrane by creation of pores within the microbial membrane ultimately results in cell death of the organism due to leakage of ions, metabolites, cessation of membrane-coupled respiration, and biosynthesis.
Several models for pore formation such as the Barrel-Stave, the Toroidal or Wormhole Model, and the Carpet Model have been proposed (Fig. 1).
Fig. 1. Mode of Action A Barrel-Stave Model B Toroidal Pore or Wormhole Model C Carpet Model
The Barrel-Stave Model
The Barrel-Stave model describes a mechanism in which AMPs form a barrellike pore within the bacterial membrane with the individual AMPs or AMP complexes being the staves. Arranged in this manner, the hydrophobic regions of the AMPs point outwards towards the acyl chains of the membrane whereas the hydrophilic areas form the pore.
The Toroidal Pore or Wormhole Model
The pores described by this model differ from those of the Barrel-Stave model. Primarily, the outer and inner leaflet of the membrane are not intercalated in the transmembrane channel.
The Carpet Model
A different mechanism is proposed in the Carpet model where AMPs first cover the outer surface of the membrane and then disrupt the membrane like detergents by forming micelle-like units. Certain AMPs penetrate the bacterial membrane without channel formation. They act on intracellular targets by e.g. inhibiting nucleic acid and/or protein synthesis.
Resistance to AMPs can either be constitutive or inducible. Inherited resistance mechanisms include altered surface charge, active efflux, production of peptidases or trapping proteins, and modification of host cellular processes. For instance, Staphylococcus aureus manages to reduce the overall cell surface charge by esterification of the cell wall component teichoic acid with D-alanine and thereby increases its resistance against human AMPs. Another example for changing the surface net charge is the production of cationic lysine-substituted phosphatidylglycerol (L-PG) found in certain Staphylococcus aureus strains. In Gram-negative bacteria, addition of 4-aminoarabinose (Ara4N) to the phosphate group of the lipid A backbone or increased acylation of lipopolysaccharides (LPS) are important mechanisms of AMP resistance. Exposure to AMPs may also induce stress responses by which microorganisms try to survive. Inducible regulatory mechanisms have been described in a variety of organisms. For instance, the PhoP/PhoQ regulon in Salmonella has been demonstrated to regulate transcriptional activation of surface and secretory proteins, enzymes that modify lipopolysaccharide, lipid and protein constituents of the outer membrane and proteases that likely degrade certain AMPs.
Examples of antimicrobial peptides
|Cationic peptides enriched for specific|
|Glycine-containing peptides||Hymenoptaecin from honeybees|
|Glycine- and proline-containing peptides||Coleoptericin from beetles
Holotricin from beetles
|Histidine-containing peptides||Histatins from humans and some higher primates|
|Proline-containing peptides||Abaecin from honeybees|
|Proline- and arginine-containing peptides||Apidaecins from honeybees
Bactenicins from cattle
Drosocin from Drosophila
PR-39 from pigs
|Proline- and phenylalanine-containing peptides||Prophenin from pigs|
|Tryptophan-containing peptides||Indolicidin from cattle|
|Linear cationic α-helical peptides|
|Andropin from insects
Bombinin from amphibians
Buforin II from amphibians
CAP18 from rabbits
Cepropins from insects
Cecropin P1 from the pig intestinal parasitic nematode,
Ceratotoxin from insects
Dermaseptin from amphibians
LL-37 from human
Magainin from amphibians
Melittin from insects
Pleurocidin from Pseudopleuronectes americanus
|Anionic and cationic peptides that contain|
cysteine and form disulfide bonds
|1 Disulfide bond||Brevinins|
|2 Disulfide bonds||Protegrins from pigs|
|3 Disulfide bonds||α-Defensins from human, rabbits and rats
β-Defensins from humans, cattle, mice, rats, pigs, goats
θ-Defensin from the rhesus monkey
Insect defensins (Defensin-A from Aedes aegypti)
|4 Disulfide bonds||Antifungal defensins from plants
Drosomycin from Drosophila
|Anionic peptides||Dermcidin from human skin
Maximin H5 from amphibian skin
|Anionic and cationic peptide fragments|
derived from precursor proteins
|Antimicrobial domains from bovine α-lactalbumin, human
hemoglobin, lysozyme, and ovalbumin
Aromatic dipeptides from dipteran larvae
Casocidin I from human casein
Enkelytin from proenkaphalin A
Lactoferricin from lactoferrin
The structures of AMPs represent a unique source for the targeted exploration of new applications in the therapy of microbial and viral infection, cancer, and sepsis. Modern synthetic methods will allow the relatively cheap and accurate production of lead compounds and peptide candidates. The achievements in peptide library generation, analytical methods as mass spectrometry, and screening and formulation technologies may contribute to solve intrinsic problems associated with the use of AMPs as therapeutic agents such as susceptibility to proteases and host toxicity. Bachem has considerable expertise and long-standing experience in peptide synthesis. With our capacity to upscale the production of simple and modified peptides, we are the partner of choice for the pharmaceutical industries.
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E. Martin et al.
Defensins and other endogenous peptide antibiotics of vertebrates.
J. Leukoc. Biol. 58, 128-136 (1995)
D. Andreu and L. Rivas
Animal antimicrobial peptides: an overview.
Biopolymers 47, 415-433 (1998)
R.E. Hancock and D.S. Chapple
Antimicrob. Agents Chemother. 43, 1317-1323 (1999)
Antimicrobial peptides of multicellular organisms.
Nature 415, 389-395 (2002)
Antimicrobial peptides in defence of the oral and respiratory tracts.
Mol. Immunol. 40, 431-443 (2003)
A.E. Shinnar et al.
Cathelicidin family of antimicrobial peptides: proteolytic processing and protease resistance.
Bioorg. Chem. 31, 425-436 (2003)
M.R. Yeaman and N.Y. Yount
Mechanisms of antimicrobial peptide action and resistance.
Pharmacol. Rev. 55, 27-55 (2003)
T. Jin et al.
Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism.
J. Immunol. 172, 1169-1176 (2004)
Theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins.
Curr. Protein Pept. Sci. 5, 365-371 (2004)
Cathelicidins, multifunctional peptides of the innate immunity.
J. Leukoc. Biol. 75, 39-48 (2004)
Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?
Nat. Rev. Microbiol. 3, 238-250 (2005)
The role of cathelicidins in the innate host defenses of mammals.
Curr. Issues Mol. Biol. 7, 179-196 (2005)
H. Jenssen et al.
Peptide antimicrobial agents.
Clin. Microbiol. Rev. 19, 491-511 (2006)
Antimicrobial peptide resistance mechanisms of human bacterial pathogens.
Curr. Issues Mol. Biol. 8, 11-26 (2006)
Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide.
Ann. Agric. Environ. Med. 14, 1-4 (2007)
D.W. Hoskin and A. Ramamoorthy
Studies on anticancer activities of antimicrobial peptides.
Biochim. Biophys. Acta 1778, 357-375 (2008)
J. Schauber and R.L. Gallo
Antimicrobial peptides and the skin immune defense system.
J. Allergy Clin. Immunol. 122, 261-266 (2008)
H. Suttmann et al.
Antimicrobial peptides of the cecropin-family show potent anti-tumor activity against bladder cancer cells.
BMC Urol. 8, 5 (2008)
K. Yamasaki and R.L. Gallo
Antimicrobial peptides in human skin disease.
Eur. J. Dermatol. 18, 11-21 (2008)
G. Diamond et al.
The roles of antimicrobial peptides in innate host defense.
Curr. Pharm. Des. 15, 2377-2392 (2009)
Y. Lai and R.L. Gallo
AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense.
Trends Immunol. 30, 131-141 (2009)
A. Nijnik and R.E. Hancock
The roles of cathelicidin LL-37 in immune defences and novel clinical applications.
Curr. Opin. Hematol. 16, 41-47 (2009)
Bacterial sensing of antimicrobial peptides.
Contrib. Microbiol. 16, 136-149 (2009)
R. Palffy et al.
On the physiology and pathophysiology of antimicrobial peptides.
Mol. Med. 15, 51-59 (2009)
M. Simmaco et al.
Bombinins, antimicrobial peptides from Bombina species.
Biochim. Biophys. Acta 1788, 1551-1555 (2009)
A. Zairi et al.
Dermaseptins and magainins: antimicrobial peptides from frogs’ skin-new sources for a promising spermicides microbicides-a mini review.
J. Biomed. Biotechnol. 2009, 452567 (2009)
The human cathelicidin hCAP18/LL-37: a multifunctional peptide involved in mycobacterial infections.
Peptides 31, 1791-1798 (2010)
J. Wiesner and A. Vilcinskas
Antimicrobial peptides: the ancient arm of the human immune system.
Virulence 1, 440-464 (2010)
C.D. Fjell et al.
Designing antimicrobial peptides: form follows function.
Nat. Rev. Drug Discov. 11, 37-51 (2012)
K. Parn et al.
The antimicrobial and antiviral applications of cell-penetrating peptides.
Methods Mol. Biol. 1324, 223-245 (2015)