Title: Interaction of the Antimicrobial Polymyxin B1 with the Inner and Outer Membranes of E.Coli: Insights into the Mechanisms of Membrane Disruption
Abstract: Antimicrobial peptides (AMPs) are small proteins that show antimicrobial activity against bacteria, fungi and viruses. They disrupt bacterial membranes by increasing the membrane permeability and pore formation. AMPs can be found in most living organisms where they have been shown to play an essential part of the innate immunity. With the increasing number of bacterial strains acquiring resistance to current antibiotics, the need for novel antibiotics is urgent. Polymyxin B1 (PMB1) is a small antimicrobial peptide first derived from the bacteria Bacilus Polymyxa in 1947. It is a highly active antimicrobial peptide and shows selectivity predominantly to gram-negative bacteria. It has been shown to be successful in treating infections caused by the bacteria Pseudomonas aeruginosa with little development of resistance. After recent studies have shown that its toxicity may have been exaggerated in the past, interest has been renewed in this AMP. The exact mechanism of membrane disruption by PMB1 is not known. To address this we have conducted a molecular dynamics simulation study to investigate the potential structure related properties this AMP possesses that enables it to disrupt bacterial membranes. To study these properties we simulated PMB1 in three different membrane environments, mimics of the outer membrane of Gram-negative bacteria, the inner membrane, and also a symmetric lipid A bilayer. Our results provide the first molecular-level insights of this antimicrobial peptide inserting into realistic, complex bacterial membranes.