Lipid Selectivity of Fungicidal Lipopeptides

Abstract

Gram-negative bacteria such as E.coli are protected by a surprisingly complex cell envelope. The cell envelope is composed of two membranes that form a protective barrier around the cells, and control the influx and efflux of solutes via various routes. Lysing the cell by disrupting the membranes, or permeating across them to gain access to the cell interior are key properties for antimicrobial agents. Polymyxins are a class of antibiotics that have been shown to be highly active against Gram-negative bacteria. It is thought they enter bacterial cells through a self-uptake mechanism, although the molecular details of the mechanism are still unclear. We present, to our knowledge, the first molecular dynamics simulation study of an antimicrobial peptide, with both membranes of E.coli. Our model of the outer membrane contains lipopolysaccharide molecules in the inner leaflet and a mixture of ohosphilipids in the inner leaflet. In contrast, the inner membrane is comprised only of phospholipids. Our simulations reveal the effects of Polymyxin B1 (PMB1) binding on the physical properties of each membrane. Thus they are able to identify potentially different mechanisms for membrane disruption by PMB1. Peptide aggregation and insertion of one peptide tail was observed in the outer membrane. In contrast, PMB1 peptides insert readily as monomers, accompanied by water penetration into the inner membrane. Our simulations demonstrate the importance of capturing relevant details of biological complexity, in molecular models of biological membrane systems.

The Optimal Lipid Chain Length of a Membrane-Permeabilizing Lipopeptide Results From the Balance of Membrane Partitioning and Local Damage

“…To test the hypothesis that these chain-length effects may be due to rather unspecific bilayer interactions, we selected POPC liposomes as a generic membrane model examining only this level of interactions. This approach deliberately eliminates other important, potential determinants of lipid selectivity ( Fiedler et al, 2015 ) that may arise from specific lipids contained in the outer and inner leaflet of the plasma membranes of gram-positive bacteria. This aims at assigning chain length effects on activity and selectivity to their underlying molecular interactions; it does not attempt modeling the bacterial membrane as good as possible.…”

Effects of Cholesterol on the mechanism of fengycin, a biofungicide

“…(1) The purported presence of pores suggests that fengycin must aggregate on the membrane surface in order to function, and although no experiments have been able to demonstrate this effect directly, Fiedler et al hypothesized that fengycins preferentially interact with cholesterols and thus are unable to aggregate, reducing membrane permeabilization. (31) Molecular dynamics simulations are an excellent tool to fill in this missing connection, since their molecule-scale resolution neatly matches the problem. However, obtaining sufficient sampling still remains an issue; lateral reorganization of the membrane and protein conformational change are both slow processes compared to the timescale of most molecular dynamics simulations.…”