Gram-positive bacterial cell envelopes: The impact on the activity of antimicrobial peptides

Abstract

A number of cationic antimicrobial peptides, effectors of innate immunity, are supposed to act at the cytoplasmic membrane leading to permeabilization and eventually membrane disruption. Thereby, interaction of antimicrobial peptides with anionic membrane phospholipids is considered to be a key factor in killing of bacteria. Recently, evidence was provided that killing takes place only when bacterial cell membranes are completely saturated with peptides. This adds to an ongoing debate, which role cell wall components such as peptidoglycan, lipoteichoic acid and lipopolysaccharide may play in the killing event, i.e. if they rather entrap or facilitate antimicrobial peptides access to the cytoplasmic membrane. Therefore, in this review we focused on the impact of Gram-positive cell wall components for the mode of action and activity of antimicrobial peptides as well as in innate immunity. This led us to conclude that interaction of antimicrobial peptides with peptidoglycan may not contribute to a reduction of their antimicrobial activity, whereas interaction with anionic lipoteichoic acids may reduce the local concentration of antimicrobial peptides on the cytoplasmic membrane necessary for sufficient destabilization of the membranes and bacterial killing. Further affinity studies of antimicrobial peptides toward the different cell wall as well as membrane components will be needed to address this problem on a quantitative level. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Antimicrobial Peptides: Mechanisms of Action and Resistance

“…In gram-positive bacteria, D-alanylation of wall teichoic and lipoteichoic acids reduces the net negative charge and confers relative protection against AMPs (Koprivnjak and Peschel 2011;Simanski et al 2013;Malanovic and Lohner 2016). Thus, dlt mutants, which are unable to D-alanylate teichoic acids, are relatively more susceptible to killing by cationic AMPs (Simanski et al 2013).…”

“…It is thus quite likely that a given peptide can cause different effects on phospholipid membranes, depending on lipid composition, temperature, and other environmental factors, and such interactions are best described by phase diagrams (Bechinger and Lohner 2006). The differences in membrane lipid composition of bacterial strains (Cheng et al 2011;Malanovic and Lohner 2016) and the distinct environment that they need to propagate may thus contribute to the variable selectivity and activity of AMPs. A recent investigation showed that MP196, an arginine-rich minimalistic AMP, and gramicidin compete with the association of peripheral membrane proteins (Wenzel et al 2014), an effect that is probably driven by electrostatic interactions and may further modulate peptide action at the membrane surface.…”

“…Once AMPs have crossed the outer barriers-represented by the outer membrane and cell wall, respectively-their interaction with the plasma membrane and internal targets may follow similar mechanisms (Koprivnjak and Peschel 2011;Malanovic and Lohner 2016).…”

“…On one hand, the cell wall of gram-positive bacteria represents a porous 40-to 80-nm-thick mesh that many AMPs seem to pass with relative ease (Malanovic and Lohner 2016). On the other, gram-negative bacteria present an outer membrane that some AMPs can quickly cross by a charge-exchange mechanism where the cationic peptides compete with Ca 2+ and Mg 2+ bound to lipopolysaccharide, possibly promoted by binding to outer membrane proteins (self-promoted uptake hypothesis; e.g., Anunthawan et al 2015).…”

Lipid-packing perturbation of model membranes by pH-responsive antimicrobial peptides

“…This lack of discrimination indicates that these peptides act directly on the lipid matrix of the cell membrane, with no requirement for specific membrane receptors (Hancock et al 1995;Shai 1999;Epand and Vogel 1999;Zasloff 2002). The outer leaflet of the plasma membrane of prokaryotic cells is rich in anionic phospholipids (Malanovic and Lohner 2015), while the surface of the eukaryotic cells is electrostatically neutral due to the dominance of zwitterionic and uncharged lipids (Rothman and Lenard 1977;Devaux 1991). Due to their cationicity, antimicrobial peptides have a preference for anionic membranes, driven mostly by electrostatic interactions between them.…”