Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria.
A synthetic peptide, KFFKFFKFFK [corrected], consisting of cationic lysine residues and hydrophobic phenylalanine residues was found to sensitize gram-negative bacteria to hydrophobic and amphipathic antibiotics. At a concentration of 3 micrograms/ml, it decreased the MIC of rifampin for smooth, encapsulated Escherichia coli by a factor of 300. Other susceptible bacterial species included Enterobacter cloacae, Klebsiella pneumoniae, and Salmonella typhimurium, but Pseudomonas aeruginosa was resistant. Similar results were obtained with another synthetic peptide, IKFLKFLKFLK [corrected]. The fractional inhibitory concentration indices for the synergism of these peptides with rifampin, erythromycin, fusidic acid, and novobiocin were very close to those determined for the previously characterized potent outer-membrane-disorganizing agents polymyxin B nonapeptide and deacylpolymyxin B. KFFKFFKFFK [corrected] had direct activity against the gram-positive organism Micrococcus strain ML36, was strongly hemolytic, and was as active on polymyxin-resistant E. coli mutants as on their parent. These three attributes made KFFKFFKFFK [corrected] different from polymyxin derivatives and similar to cationic detergents, such as cetylpyridinium chloride. However, whereas the MIC of cetylpyridinium chloride for E. coli is low (0.5 to 4 micrograms/ml), that of KFFKFFKFFK [corrected] is much higher (30 to 100 micrograms/ml). Other groups of synthetic peptides studied included polymyxin-like peptides with an intrachain disulfide bridge. Their synergism with antibiotics was less marked. Still other peptides, including KEKEKEKEKE and KKKKKKFLFL, lacked any synergism with the probe antibiotics.
Vaara
M
M
Department of Bacteriology and Immunology, University of Helsinki, Finland. Martti.Vaara@Helsinki.Fi
Porro
M
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects*; D004917:Erythromycin / Q000494:pharmacology; D005672:Fusidic Acid / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008837:Micrococcus / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D009842:Oligopeptides; D005672:Fusidic Acid; D004917:Erythromycin; D012293:Rifampin