Revealing the Mechanisms of Synergistic Action of Two Magainin Antimicrobial Peptides

Abstract

The study of peptide-lipid and peptide-peptide interactions as well as their topology and dynamics using biophysical and structural approaches have changed our view how antimicrobial peptides work and function. It has become obvious that both the peptides and the lipids arrange in soft supramolecular arrangements which are highly dynamic and able to change and mutually adapt their conformation, membrane penetration, and detailed morphology. This can occur on a local and a global level. This review focuses on cationic amphipathic peptides of the magainin family which were studied extensively by biophysical approaches. They are found intercalated at the membrane interface where they cause membrane thinning and ultimately lysis. Interestingly, mixtures of two of those peptides namely magainin 2 and PGLa which occur naturally as a cocktail in the frog skin exhibit synergistic enhancement of antimicrobial activities when investigated together in antimicrobial assays but also in biophysical experiments with model membranes. Detailed dose-response curves, presented here for the first time, show a cooperative behavior for the individual peptides which is much increased when PGLa and magainin are added as equimolar mixture. This has important consequences for their bacterial killing activities and resistance development. In membranes that carry unsaturations both peptides align parallel to the membrane surface where they have been shown to arrange into mesophases involving the peptides and the lipids. This supramolecular structuration comes along with much-increased membrane affinities for the peptide mixture. Because this synergism is most pronounced in membranes representing the bacterial lipid composition it can potentially be used to increase the therapeutic window of pharmaceutical formulations.

Antimicrobial peptides: features, applications and the potential use against covid-19

“…The structure of α-helical peptides is lost in solution, but acquires an amphipathic helical structure in contact with a biological membrane. Frog magainins belong to this class [ 21 ]. On the other hand, β-Sheet peptides contain two to ten cysteine residues that form one to five interchain disulfide bonds.…”

Physicochemical Features and Peculiarities of Interaction of AMP with the Membrane

“…At the same time, it should be noted that biological membranes mainly consist of unsaturated lipids. It has been shown that in membranes that carry unsaturations, both peptides are aligned along the bilayer surface [173]. Consequently, a mechanism for synergistic antibacterial activities should necessarily consider the last fact.…”

Different Biological Activities of Histidine-Rich Peptides Are Favored by Variations in Their Design

“…The pronounced antimicrobial activities of cationic amphipathic peptides including LAH4 sequences have been associated with the perforation of microbial membranes [10,18,51,52,55]. Indeed, under conditions where the peptides align along the membrane surface [11,13,20], high concentrations of LAH4 peptides result in the lysis of lipid bilayers [17,22].…”

“…Cecropins and magainins were among the first peptides from higher organisms for which a wide range of antimicrobial activities was described [8]. Early on after their discovery, biophysical approaches showed that these peptides are aligned along the surface of lipid bilayers rather than forming channels made of transmembrane helical bundles, as had initially been considered [9,10]. To further investigate the interaction contributions that govern peptide-membrane interactions, histidine-rich peptides were designed by assembling an alanine-leucine hydrophobic core, interspersed with four histidines (LAH4) that all align at one face in a helical conformation, and two lysines at each terminus [11].…”