Lipopeptide-induced changes in permeability of solid supported bilayers composed of bacterial membrane lipids

Lipopeptides are known to show bactericidal activity and due to their simple structure, ease of design, and low cost of implementation, they are often considered potent replacement for many traditional antibiotics. Another important advantage of lipopeptides is related to the fact that their preferential target is a cell membrane. Hence their action is less specific than conventional antibiotics, which means that development of drug resistance by pathogens is less probable in such case. In this paper we have utilized electrochemical methods and in situ atomic force microscopy to evaluate the mode of action of novel lipopeptide C15H31CO-DPhe-Dab-Dab-Leu-NH2 on planar lipid bilayer. The latter was composed of phosphatidylethanolamines and phosphatidylglycerols extracts from E. coli. Therefore it can be considered as a simplified model of inner membrane of Gram negative bacteria. We have found that lipopeptide-lipid interactions strongly affect molecular organization of PE/PG bilayer, which is reflected by increased disorder and subsequent perforation of the film. Importantly, fluid domains were identified as preferential sites for insertion of lipopeptide molecules, which tend to accumulate within the membrane. However, above certain threshold ratio the membrane becomes swollen and strongly destabilized. This results in membrane rupture and large mixed lipopeptide-lipid aggregates departure from electrode surface. Based on experimental observations, the mechanism of C16-fXXL action on bacterial-like model membrane is proposed.