Regulation of Antimicrobial Peptide Activity via Tuning Deformation Fields by Membrane-Deforming Inclusions.

Oleg V Kondrashov,Sergey A Akimov

doi:10.3390/ijms23010326

Abstract

Antimicrobial peptides (AMPs) are considered prospective antibiotics. Some AMPs fight bacteria via cooperative formation of pores in their plasma membranes. Most AMPs at their working concentrations can induce lysis of eukaryotic cells as well. Gramicidin A (gA) is a peptide, the transmembrane dimers of which form cation-selective channels in membranes. It is highly toxic for mammalians as being majorly hydrophobic gA incorporates and induces leakage of both bacterial and eukaryotic cell membranes. Both pore-forming AMPs and gA deform the membrane. Here we suggest a possible way to reduce the working concentrations of AMPs at the expense of application of highly-selective amplifiers of AMP activity in target membranes. The amplifiers should alter the deformation fields in the membrane in a way favoring the membrane-permeabilizing states. We developed the statistical model that allows describing the effect of membrane-deforming inclusions on the equilibrium between AMP monomers and cooperative membrane-permeabilizing structures. On the example of gA monomer-dimer equilibrium, the model predicts that amphipathic peptides and short transmembrane peptides playing the role of the membrane-deforming inclusions, even in low concentration can substantially increase the lifetime and average number of gA channels.

Highlights

Antimicrobial peptides (AMP) are considered as prospective candidates for the generation of antibiotics; they are thought to be able to overcome multiple drug resistances of bacteria
Here we develop the statistical model for conductivity of the membrane induced by gramicidin A, the consideration can be generalized for other types of AMPs inducing elastic deformations
We demonstrate that even low concentrations of amphipathic peptides (e.g., 1 peptide per 2500 lipids) and extremely low concentrations of short transmembrane peptides (e.g., 1 peptide per 100,000 lipids) are sufficient to substantially alter the average characteristics of the Gramicidin A (gA) channel ensemble

Summary

Introduction

Antimicrobial peptides (AMP) are considered as prospective candidates for the generation of antibiotics; they are thought to be able to overcome multiple drug resistances of bacteria. The selectivity of AMPs towards bacteria is mainly based on negative electric charge of the outer leaflet of bacterial plasma membrane, as opposed to electrically neutral outer leaflets of membrane of eukaryotic cells. The characteristic feature of amphipathic peptides having α-helical secondary structure is that their helix has one predominantly hydrophobic side surface, while the opposite side surface is mainly polar and charged. The ratio of hydrophobic/hydrophilic areas determines the so-called polar angle, which is considered to be responsible for the type of the pore formed by the peptides: larger polar angle yields barrel-like pores. AMPs having β-sheet secondary structure mostly form barrel-like pores of fixed stoichiometry, and, fixed pore diameter and conductivity [3]

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Conclusion