Can Peptide-Lipid Interactions Predict Bactericidal and Hemolytic Activity in Antimicrobial Peptides?

Abstract

It is relatively simple to design highly amphipathic linear cationic beta-sheet peptides containing 10-to-11 amino acids that possess potent antimicrobial activity. Often, however, these peptides also are quite hemolytic, so that there is insufficient selectivity between bacterial and human cells. Peptides with little or no hemolytic (or other toxic) activity toward human cells at 100 or more times the minimum inhibitory concentrations toward bacterial cells might be potential candidates for clinical use as antimicrobials. Since these peptides typically exert their bactericidal action through membrane disruption, we are interested in how they interact with model lipid vesicles. Here, we investigated how a group of peptides all containing a single tryptophan residue interact with large unilamellar vesicles (LUV) consisting of either anionic phosphatidylglycerol (PG), neutral phosphatidylcholine (PC), mimicking a mammalian plasma membrane surface, or a 2:1 mixture of phosphatidylethanolamine (PE) and PG, mimicking an E. coli plasma membrane surface. Lipid-peptide interactions are assessed by: (1) peptide conformation using circular dichroism; (2) proteolytic degradation; and (3) quenching of tryptophan fluorescence by aqueous acrylamide and membrane-bound 10-doxyl-nonadecane. By comparing results in the absence and presence of LUV, we assessed three sets of peptides with (a) high antimicrobial and high hemolytic activity, (b) low antimicrobial and low hemolytic activity, and (c) high antimicrobial and low hemolytic activity. Our results demonstrate that the ability of these peptides to interact with LUV of defined lipid composition in most cases correlates well with their activities in bacterial and human cells.