Mechanism of Bacterial Resistance to Antimicrobial Peptides

Antibiotic resistance continues to emerge and intensify. Antimicrobial peptides (AMPs) are a promising alternative to current antibiotics, but bacteria have also evolved a range of resistance mechanisms to AMPs, which include thickening of the cell wall, modification of the phospholipid composition, changing the net surface charge, increasing the membrane fluidity, releasing proteinases to degrade the peptides and discharging amino acids into the environment to reduce hypo-osmotic stress. While much is known about the proteins that are mutated or are involved in resistance mechanisms, little is known about how membrane structure and properties influence the ability of microbes to resist AMP action. Given our increasing understanding of the relationship between membrane properties and cellular function, it is imperative that we now more fully characterise how bacteria transiently modify their lipid content and repel the action of AMPs. We hypothesise that the membrane properties play a central role in the development of resistance to the action of AMPs and that, understanding how phospholipid composition changes impact on AMP function, will lead to new antimicrobial strategies. This project aims to 1) examine the changes in bacterial membrane lipid profile upon exposure to AMPs; 2) determine the mechanism of binding, peptide orientation and the effect on membrane morphology of AMPs; and 3) determine the reversible changes in real time of bacterial membranes following AMP exposure and recovery. These studies will provide a detailed understanding of the molecular basis for the membrane-mediated resistance to AMPs, specifically, how activity is related to differences in the composition of mammalian and microbial membranes and how the membrane barrier can be more effectively targeted with agents tailored to lyse compositionally different membranes.