title: A novel form of bacterial resistance to the action of eukaryotic host defense peptides, the use of a lipid receptor.
abstract: 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 (Kd > 225 μM) while showing a strong ability to lyse (>55%) and penetrate (π > 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 (Kd < 65 μM) and showed a very low ability for bilayer lysis (<8%) and partitioning (π > 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.
authors.affiliation: School of Pharmacy and Biomedical Sciences, †School of Forensic and Investigative Sciences, and ‡School of Computing, Engineering and Physical Sciences, University of Central Lancashire , Preston, PR1 2HE, U.K.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Dennison
authors.forename: Frederick
authors.initials: F
authors.lastname: Harris
authors.forename: Manuela
authors.initials: M
authors.lastname: Mura
authors.forename: Leslie H G
authors.initials: LH
authors.lastname: Morton
authors.forename: Andrei
authors.initials: A
authors.lastname: Zvelindovsky
authors.forename: David A
authors.initials: DA
authors.lastname: Phoenix
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002942:Circular Dichroism; D004352:Drug Resistance, Microbial; D008055:Lipids / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D008055:Lipids; D010455:Peptides; D011956:Receptors, Cell Surface