Antimicrobial lipopeptides

Antimicrobial peptides (AMPs) are, as the name suggests, peptides excreted by cells to protect them from pathogens in the environment. All multicellular organisms use AMPs as a component of their immune systems. These peptides function primarily by targeting the cell membranes; selectivity for pathogens is based on differences in the lipid compositions of their cell membranes. For example, bacteria tend to have a high concentration of anionic lipids in their outer membranes, while eukaryotic cell membranes are largely zwitterionic; it is not surprisingly that the vast majority of the 2000 AMPs known are cationic.

Following the discovery of the magainin class of AMPs in frog skin in the 1980s, the community became very interested in developing AMPs as antibiotics. However, their initial promise has not for the most part paid off in new drugs. AMPs have two major weaknesses as drugs. First, natural AMPs range from 12-50 residues in length; while this makes them relatively small as biomolecules, they are far larger than typical drugs, with the result that they are expensive to produce and handle in large quantities. Second, the peptide backbone is vulnerable to digestion by peptidases, reducing the viability of AMPs as internal drugs.

With these strengths and weaknesses in mind, we have been investigating the properties of a class of synthetic molecules termed antimicrobial lipopeptides (AMLPs). Specifically, the molecules wefocus on are very short cationic peptides (4-6 residues), with a fatty acid attached to the N-terminus. The molecules have antibacterial and antifungal properties, with minimum inhibitory concentrations in the micromolar range. However, their mechanism is not understand at the molecular level. The goal of our research is to understand how AMLPs target and damage bacterial membranes, and how their achieve selectivity to avoid damaging mammalian membranes. To do this, we use a combination of all-atom and coarse-grained molecular dynamics simulations.