title: Enhanced membrane disruption and antibiotic action against pathogenic bacteria by designed histidine-rich peptides at acidic pH.
abstract: The histidine-rich amphipathic cationic peptide LAH4 has antibiotic and DNA delivery capabilities. Here, we explore the interaction of peptides from this family with model membranes as monitored by solid-state (2)H nuclear magnetic resonance and their antibiotic activities against a range of bacteria. At neutral pH, the membrane disruption is weak, but at acidic pH, the peptides strongly disturb the anionic lipid component of bacterial membranes and cause bacterial lysis. The peptides are effective antibiotics at both pH 7.2 and pH 5.5, although the antibacterial activity is strongly affected by the change in pH. At neutral pH, the LAH peptides were active against both methicillin-resistant and -sensitive Staphylococcus aureus strains but ineffective against Pseudomonas aeruginosa. In contrast, the LAH peptides were highly active against P. aeruginosa in an acidic environment, as is found in the epithelial-lining fluid of cystic fibrosis patients. Our results show that modest antibiotic activity of histidine-rich peptides can be dramatically enhanced by inducing membrane disruption, in this case by lowering the pH, and that histidine-rich peptides have potential as future antibiotic agents.
authors.affiliation: Faculté de Chimie, University Louis Pasteur, Institut le Bel, Strasbourg, France. jmason@chimie.u-strasbg.fr
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
authors.forename: Claire
authors.initials: C
authors.lastname: Gasnier
authors.forename: Antoine
authors.initials: A
authors.lastname: Kichler
authors.forename: Gilles
authors.initials: G
authors.lastname: Prévost
authors.forename: Dominique
authors.initials: D
authors.lastname: Aunis
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Metz-Boutigue
authors.forename: Burkhard
authors.initials: B
authors.lastname: Bechinger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001424:Bacterial Infections / Q000382:microbiology; D002462:Cell Membrane / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D054806:Magainins; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014981:Xenopus; D029867:Xenopus Proteins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C122154:LAH(4) protein, synthetic; D054806:Magainins; D010455:Peptides; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus