Mode of action of linear amphipathic α‐helical antimicrobial peptides

Abstract

The increasing resistance of bacteria to conventional antibiotics resulted in a strong effort to develop antimicrobial compounds with new mechanisms of action. Antimicrobial peptides seem to be a promising solution to this problem. Many studies aimed at understanding their mode of action were described in the past few years. The most studied group includes the linear, mostly alpha-helical peptides. Although the exact mechanism by which they kill bacteria is not clearly understood, it has been shown that peptide-lipid interactions leading to membrane permeation play a role in their activity. Membrane permeation by amphipathic alpha-helical peptides can proceed via either one of the two mechanisms: (a) transmembrane pore formation via a "barrel-stave" mechanism; and (b) membrane destruction/solubilization via a "carpet-like" mechanism. The purpose of this review is to summarize recent studies aimed at understanding the mode of action of linear alpha-helical antimicrobial peptides. This review, which is focused on magainins, cecropins, and dermaseptins as representatives of the amphipathic alpha-helical antimicrobial peptides, supports the carpet-like rather the barrel-stave mechanism. That these peptides vary with regard to their length, amino acid composition, and next positive charge, but act via a common mechanism, may imply that other linear antimicrobial peptides that share the same properties also share the same mechanism.

Synthetic mimics of antimicrobial peptides

“…They also identified cooperative interactions between the SMAMPs residing just below the head group region. The conclusions emphasized SMAMP cooperativity, which is also central to the traditional Shai‐Matsuzaki‐Huang (SMH) model of membrane disruption 20, 21, 68. However, no evidence was found for the formation of pores when the SMAMPs oligomerized on the membrane surface.…”

“…Several models, such as the toroidal pore , carpet ‐like, and barrel stave , have been proposed to explain the complex structures formed between lipids and various AMPs during their interactions (see references for detail of these mechanisms) 8, 20–22. It is thought that electrostatic interactions facilitate association of the peptide with the anionic bacterial membrane 9, 23.…”

“…Self‐assembly of several β‐peptide molecules within the bilayer was assumed to aid pore formation by altering the membrane curvature. These two β‐peptides conformed to the SMH model, which has been developed to explain the mode of action of cationic AMPs 20, 21, 68…”

Nontoxic Membrane‐Active Antimicrobial Arylamide Oligomers

“…The selectivity of natural antimicrobial peptides for lysing bacterial rather than mammalian cells depends on the appropriate balance of conformational rigidity, hydrophobicity, and the distribution of charged side chains in the peptide 14. 17, 18 If the compounds are too polar they have little affinity for bacterial membranes; if they are too hydrophobic they fail to discriminate between mammalian and bacterial targets.…”

Soy isoflavones enhance β‐defensin synthesis and secretion in endometrial epithelial cells with exposure to TLR3 agonist polyinosinic‐polycytidylic acid

“…β‐defensins (BDs), one of the most important families of AMPs, play a crucial role in immune host defense by exhibiting broad‐spectrum antimicrobial activity against pathogen infection. BDs cause microbial death by permeabilization of the membrane due to pore formation and/or by altering the intracellular signaling and inhibiting nucleic acid synthesis. In addition to antimicrobial activity, they exert chemotactic activity by recruiting immature dendritic cells, memory T cells, and neutrophils to the site of infection by binding to the chemokine receptor CCR6.…”