A novel form of bacterial resistance to the action of eukaryotic host defense peptides, the use of a lipid receptor

Dennison, Sarah R., Harris, Frederick, Mura, Manuela , Morton, Leslie H. G., Zvelindovsky, Andrei and Phoenix, David A. (2013) A novel form of bacterial resistance to the action of eukaryotic host defense peptides, the use of a lipid receptor. Biochemistry, 52 (35). pp. 6021-6029. ISSN 0006-2960

Full content URL: http://pubs.acs.org/doi/abs/10.1021/bi400719j

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A novel form of bacterial resistance to the action of eukaryotic host defense peptides, the use of a lipid receptor

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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 (R2 = 0.96) but inversely correlated with its lytic ability (R2 = 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. © 2013 American Chemical Society.

Keywords:Ammonium groups, Bacterial resistance, Bi-layer, Charge-charge interactions, Host defense, N-terminals, Phosphoethanolamine, Resistance mechanisms, Computer simulation, Escherichia coli, Hydrogen bonds, Membranes, Peptides, 1,2 dimyristoyl sn glycero 3 phosphoethanolamine, 4 (2 hydroxyethyl) 1 piperazineethanesulfonic acid, ammonia, ampholyte, anionic surfactant, calcimycin, lipid receptor, lysophospholipid receptor, peptide, phosphate, unclassified drug, amino terminal sequence, antibiotic resistance, article, bacterial membrane, bacterial strain, bilayer membrane, binding affinity, Bombina maxima, chemical interaction, controlled study, eukaryote, host resistance, hydrogen bond, hydrophobicity, lipid bilayer, lysis, priority journal, Anti-Bacterial Agents, Circular Dichroism, Drug Resistance, Microbial, Lipids, Molecular Dynamics Simulation, Peptides, Receptors, Cell Surface
Subjects:C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Mathematics and Physics
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ID Code:14908
Deposited On:11 Sep 2014 09:41

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