A Novel Form of Bacterial Resistance to the Action of Eukaryotic Host Defense Peptides, the Use of a Lipid Receptor

Host defense peptides show great potential for development as new antimicrobial agents with novel mechanisms of action. However, a small number of resistance mechanisms to their action are known, and here, we report a novel bacterial resistance mechanism mediated by a lipid receptor. Maximin H5 from Bombina maxima bound anionic and zwitterionic membranes with low affinity (K-d > 225 mu M) while showing a strong ability to lyse (> 55%) and penetrate (pi > 6.0 mN m(-1)) these membranes. However, the peptide bound Escherichia coli and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) membranes with higher affinity (K-d < 65 mu M) and showed a very low ability for bilayer lysis (< 8%) and partitioning (pi > 1.0 mN m(-1)). Increasing levels of membrane DMPE correlated with enhanced binding by the peptide (R-2 = 0.96) but inversely correlated with its lytic ability (R-2 = 0.98). Taken with molecular dynamic simulations, these results suggest that maximin H5 possesses membranolytic activity, primarily involving bilayer insertion of its strongly hydrophobic N-terminal region. However, this region was predicted to form multiple hydrogen bonds with phosphate and ammonium groups within PE head-groups, which in concert with charge- charge interactions anchor the peptide to the surface of E. coli membranes, inhibiting its membranolytic action.