title: Antibacterial properties of an oligo-acyl-lysyl hexamer targeting Gram-negative species.
abstract: Toward developing new tools for fighting resistance to antibiotics, we investigated the antibacterial properties of a new decanoyl-based oligo-acyl-lysyl (OAK) hexamer, aminododecanoyl-lysyl-[aminodecanoyl-lysyl](5) (α(12)-5α(10)). The OAK exhibited preferential activity against Gram-negative bacteria (GNB), as determined using 36 strains, including diverse species, with an MIC(90) of 6.2 μM. The OAK's bactericidal mode of action was associated with rapid membrane depolarization and cell permeabilization, suggesting that the inner membrane was the primary target, whereas the observed binding affinity to lipoteichoic acid suggested that inefficacy against Gram-positive species resulted from a cell wall interaction preventing α(12)-5α(10) from reaching internal targets. Interestingly, perturbation of the inner membrane structure and function was preserved at sub-MIC values. This prompted us to assess the OAK's effect on the proton motive force-dependent efflux pump AcrAB-TolC, implicated in the low sensitivity of GNB to various antibiotics, including erythromycin. We found that under sub-MIC conditions, wild-type Escherichia coli was significantly more sensitive to erythromycin (the MIC dropped by >10-fold), unlike its acr-deletion mutant. Collectively, the data suggest a useful approach for treating GNB infections through overcoming antibiotic efflux.
authors: Department of Biotechnology & Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Fadia
authors: F
authors: Zaknoon
authors: Keren
authors: K
authors: Goldberg
authors: Hadar
authors: H
authors: Sarig
authors: Raquel F
authors: RF
authors: Epand
authors: Richard M
authors: RM
authors: Epand
authors: Amram
authors: A
authors: Mor
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002463:Cell Membrane Permeability; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004917:Erythromycin / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013045:Species Specificity; D013682:Teichoic Acids / Q000378:metabolism
chemical_list: C493251:AcrAB-TolC protein, Salmonella enterica; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D013682:Teichoic Acids; C009900:lipoteichoic acid; D004917:Erythromycin