Dialectics of antimicrobial peptides I: common mechanisms of offensive and protecting roles of the peptides

TL;DR

This study explores how antimicrobial peptides interact with membranes, revealing their dual offensive and protective roles, and suggests that low concentrations can prevent large pore formation, influencing antimicrobial strategies.

Contribution

It provides a comprehensive experimental and theoretical analysis of AMP-membrane interactions, highlighting the protective role of low peptide concentrations and the mechanisms behind pore formation.

Findings

AMPs make membranes permeable to protons at nanomolar levels

Low AMP concentrations prevent large pore formation

High AMP concentrations induce pore formation through ion-conducting events

Abstract

Antimicrobial peptides (AMPs) have intrigued researchers for decades due to the contradiction between their high potential against resistant bacteria and the inability to find a structure-function relationship for the development of an effective and non-toxic agent. In the present study and the companion paper [Phys. Rev. E (2024)], we performed a comprehensive experimental and theoretical analysis of various aspects of AMP-membrane interactions and AMP-induced pore formation. Using the well-known melittin and magainin as examples, we showed, using patch-clamp and fluorescence measurements, that these peptides, even at nanomolar concentrations, modify the membrane by making it permeable to protons (and, possibly, water), but not to ions, and protect the membrane from large pore formation after subsequent addition of 20-fold higher concentrations of AMPs. This protective effect is independent of the membrane side (or both sides) of the peptide addition and is determined by the peptide-induced deformations of the membrane. Peptides create small, H+-permeable pores that incessantly connect the opposing membrane leaflets, allowing translocation of peptides and lipids and thus preventing further generation of large lateral pressure/tension imbalance. At the same time, such an imbalance is a key to the formation of peptide-induced pores at high AMP concentrations, with the main contribution coming from single ion-conducting events rather than stable channel-like structures. Therefore, our results suggest that lowering the AMP concentration, which is a common principle to reduce toxicity, may actually make bacteria resistant to AMP. However, a protective pre-treatment with nanomolar concentrations of peptides may be the key to protect eukaryotic cells from the high concentrations of AMPs.