Molecular mechanisms of membrane targeting antibiotics

Abstract

The bacterial membrane provides a target for antimicrobial peptides. There are two groups of bacteria that have characteristically different surface membranes. One is the Gram-negative bacteria that have an outer membrane rich in lipopolysaccharide. Several antimicrobials have been found to inhibit the synthesis of this lipid, and it is expected that more will be developed. In addition, antimicrobial peptides can bind to the outer membrane of Gram-negative bacteria and block passage of solutes between the periplasm and the cell exterior, resulting in bacterial toxicity. In Gram-positive bacteria, the major bacterial lipid component, phosphatidylglycerol can be chemically modified by bacterial enzymes to convert the lipid from anionic to cationic or zwitterionic form. This process leads to increased levels of resistance of the bacteria against polycationic antimicrobial agents. Inhibitors of this enzyme would provide protection against the development of bacterial resistance. There are antimicrobial agents that directly target a component of bacterial cytoplasmic membranes that can act on both Gram-negative as well as Gram-positive bacteria. Many of these are cyclic peptides with a rigid binding site capable of binding a lipid component. This binding targets antimicrobial agents to bacteria, rather than being toxic to host cells. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

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“…Based on investigations on model membrane systems, diverse modes of peptide-triggered membrane permeabilization have been suggested ranging from the formation of discrete pores and detergent-like activity to more subtle mechanisms such as perturbation of lipid packing394041. The ability to trigger membrane rigidification combined with lipid domain formation, rather than membrane permeabilization or depolarisation, clearly distinguishes cWFW from other cationic AMPs.…”

Antimicrobial peptide exposure selects forStaphylococcus aureusresistance to human defence peptides

“…The antibacterial activity of AMPs can be direct by pore formation, which occurs following the interaction of positively charged, amphipathic AMPs with negatively charged bacterial cell wall components such as LPS in Gram-negative and teichoic acids (TA) in Gram-positive bacteria. 5 AMPs have also displayed bactericidal effects following translocation across the cell wall followed by inhibition of essential cellular processes. 6 …”

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents

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