title: Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus.
abstract: In previous studies, the oligo-acyl-lysyl (OAK) C12(ω7)K-β12 added to cultures of gram-positive bacteria exerted a bacteriostatic activity that was associated with membrane depolarization, even at high concentrations. Here, we report that multidrug-resistant Staphylococcus aureus strains, unlike other gram-positive species, have reverted to the sensitive phenotype when exposed to subminimal inhibitory concentrations (sub-MICs) of the OAK, thereby increasing antibiotics potency by up to 3 orders of magnitude. Such chemosensitization was achieved using either cytoplasm or cell-wall targeting antibiotics. Moreover, eventual emergence of resistance to antibiotics was significantly delayed. Using the mouse peritonitis-sepsis model, we show that on single-dose administration of oxacillin and OAK combinations, death induced by a lethal staphylococcal infection was prevented in a synergistic manner, thereby supporting the likelihood for synergism to persist under in vivo conditions. Toward illuminating the molecular basis for these observations, we present data arguing that sub-MIC OAK interactions with the plasma membrane can inhibit proton-dependent signal transduction responsible for expression and export of resistance factors, as demonstrated for β-lactamase and PBP2a. Collectively, the data reveal a potentially useful approach for overcoming antibiotic resistance and for preventing resistance from emerging as readily as when bacteria are exposed to an antibiotic alone.
authors: 1Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel. amor@tx.technion.ac.il.
authors: Galoz
authors: G
authors: Kaneti
authors: Hadar
authors: H
authors: Sarig
authors: Ibrahim
authors: I
authors: Marjieh
authors: Zaknoon
authors: Z
authors: Fadia
authors: Amram
authors: A
authors: Mor
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D010068:Oxacillin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy; D011815:R Factors / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D009842:Oligopeptides; D046915:Penicillin-Binding Proteins; D001618:beta-Lactamases; D010068:Oxacillin
keywords: OAK; host defense peptides; membrane potential; oxacillin; peptidomimetics; synergy