Molecular Mechanisms of Membrane Perturbation by Antimicrobial Peptides and the Use of Biophysical Studies in the Design of Novel Peptide Antibiotics

Abstract

Antibiotic resistant bacterial strains represent a global health problem with a strong social and economic impact. Thus, there is an urgent need for the development of antibiotics with novel mechanisms of action. There is currently an extensive effort to understand the mode of action of antimicrobial peptides which are considered as one alternative to classical antibiotics. The main advantage of this class of substances, when considering bacterial resistance, is that they rapidly, within minutes, kill bacteria. Antimicrobial peptides can be found in every organism and display a wide spectrum of activity. Hence, the goal is to engineer peptides with an improved therapeutic index, i.e. high efficacy and target specificity. For the rational design of such novel antibiotics it is essential to elucidate the molecular mechanism of action. Biophysical studies have been performed using to a large extent membrane model systems demonstrating that there are distinctive different mechanisms of bacterial killing by antimicrobial peptides. One can distinguish between peptides that permeabilize and/or disrupt the bacterial cell membrane and peptides that translocate through the cell membrane and interact with a cytosolic target. Lantibiotics exhibit specific mechanisms, e.g. binding to lipid II, a precursor of the peptidoglycan layer, either resulting in membrane rupture by pore formation or preventing cell wall biosynthesis. The classical models of membrane perturbation, pore formation and carpet mechanism, are discussed and related to other mechanisms that may lead to membrane dysfunction such as formation of lipid-peptide domains or membrane disruption by formation of non-lamellar phases. Emphasis is on the role of membrane lipid composition in these processes and in the translocation of antimicrobial peptides.

Antimicrobial Activity of Lactoferrin-Related Peptides and Applications in Human and Veterinary Medicine

“…They originate from the N-lobe of Lf, and their antimicrobial activity is chiefly linked to hydrophobicity, cationic charge, and helical conformation, which render these peptides amphiphilic molecules. Most of them cause membrane depolarization (like the antibiotics colistin and polimixin B) [46]. However, complex mechanisms, such as inhibition of the synthesis of macromolecules [47], and synergic action with host innate immunity compounds were also described [48].…”

Analysis of membrane interactions of antibiotic peptides using ITC and biosensor measurements

“…Beside non-specific membrane disturbing activities, as described for many antimicrobial peptides (AMPs) [1,2], target related modes of action are known. To date several antibiotic compounds were described, which bind to lipid anchored cell wall precursors, and thus inhibit cell wall biosynthesis.…”

Topography Studies on the Membrane Interaction Mechanism of the Eosinophil Cationic Protein

“…Antimicrobial proteins and peptides can act both at the bacteria cell wall and cytoplasmic membrane level. Because antibiotic resistance develops rapidly as soon as new agents are introduced, attempts to develop antimicrobial compounds with new mechanisms of action resulted in an increased interest in the role of antimicrobial proteins and peptides (21). A wealth of information is currently available related to the mechanism of action of antimicrobial peptides (22)(23)(24).…”