Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides

Abstract

The permeability of the bacterial outer membrane, enclosing Gram-negative bacteria, depends on the interactions of the outer, lipopolysaccharide (LPS) layer, with surrounding ions and molecules. We present a coarse-grained model for describing how cationic amphiphilic molecules (e.g., antimicrobial peptides) interact with and perturb the LPS layer in a biologically relevant medium, containing monovalent and divalent salt ions (e.g., Mg 2+ ). In our approach, peptide binding is driven by electrostatic and hydrophobic interactions and is assumed to expand the LPS layer, eventually priming it for disruption. Our results suggest that in parameter ranges of biological relevance (e.g., at micromolar concentrations) the antimicrobial peptide magainin 2 effectively disrupts the LPS layer, even though it has to compete with Mg 2+ for the layer. They also show how the integrity of LPS is restored with an increasing concentration of Mg 2+ . Using the approach, we make a number of predictions relevant for optimizing peptide parameters against Gram-negative bacteria and for understanding bacterial strategies to develop resistance against cationic peptides.

Multiple Mechanisms of the Synthesized Antimicrobial Peptide TS against Gram-Negative Bacteria for High Efficacy Antibacterial Action In Vivo

“…It is worth noting that antimicrobial peptide TS can neutralize LPSs to move through the OM LPS barrier to the bacterial intima and then destroy the intima to kill the bacteria. In addition, several scientists have found that the positively charged biological amino acids of AMPs bind to negatively charged LPSs on the OM of gram-negative bacteria through Mg 2+ and Ca 2+ ion competition [34,35]. The same result can be observed in this experiment ( Figure 5D).…”

“…Lipopolysaccharides, a major constituent of OM of gram-negative bacteria, are considered to be the first permeability barrier that blocks the entry of harmful reagents including antibiotics and host proteins [30,31]. Majority cationic antibacterial peptides can bind to negatively charged LPSs on the OM of gramnegative bacteria [32][33][34]. It is worth noting that antimicrobial peptide TS can neutralize LPSs to move through the OM LPS barrier to the bacterial intima and then destroy the intima to kill the bacteria.…”

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

“…With increasing computer power, lower resolution (coarse grain), and better algorithms for exploiting today's computer architectures, they also reveal how molecules interact and how supramolecular complexes form and evolve. MD simulations have been used, for example, to follow the insertion of hydrophobic peptides into the membrane, where they assemble into transmembrane helical bundles (Tieleman et al 2002) and how magainin interacts with lipopolysaccharides (Smart et al 2017). Furthermore, they permitted the visualization of the deformation of the lipid bilayer in the presence of in-plane oriented amphipathic peptides.…”

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

“…All-atom 100 ns simulations in palmitoyl-oleoyl-phosphatidylethanolamine/ palmitoyl-oleoyl-phosphatidylglycerol (POPE/POPG) 3/1 of one, two, or eight peptides and 512 lipids show a stable in-plane topology of magainin and pleurocidin, some oligomerization, but no pore or supramolecular rearrangement within this time frame [ 110 ]. Finally, recent simulation work investigating magainin 2-lipopolysaccharide and ion interactions shall be mentioned [ 111 ].…”