Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria

A synthetic peptide, KFFKFFKFF, 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 mu g/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, IKFLKFLKFL. 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, KFFKFFKFF 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 KFFKFFKFF 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 mu g/ml), that of KFFKFFKFF is much higher (30 to 100 mu g/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.