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

Abstract

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.

In vitro activity of MSI-78 alone and in combination with antibiotics against bacteria responsible for bloodstream infections in neutropenic patients

“…In fact, the cationic peptides allow maximal entry of several substrates into the cell. On the other hand, a general permeability-increasing effect on the cytoplasmic membrane by the peptides is not likely to be the main reason for this positive interaction and it is possible that it may be the result of a combined effect of increased access to the intracellular target for antibiotics and secondary effects of the peptide itself [13,[26][27][28]. This hypothesis could include increased uptake and accessibility to the target, combined with drugs acting on a common pathway.…”

Inhibition of Staphylococcus aureus gene expression and growth using antisense peptide nucleic acids

“…The KFFKFFKFFK peptide used in this study was originally reported as a potent permeabilizer of E. coli cells [17]. The mechanism of uptake for such peptides and their capacity to deliver cargo molecules into cells are controversial, and there is evidence for both energy-dependent and energy-independent mechanisms [18].…”

Dual antibacterial mechanisms of nisin Z against Gram-positive and Gram-negative bacteria

“…4a, nisin Z at 5 nM efficiently caused permeabilisation of the S. aureus cytoplasmic membrane, whereas pre-treatment of S. aureus with 500 M vancomycin prior to nisin Z incubation completely inhibited the cytoplasmic membrane permeabilisation. To compare nisin Z with other antimicrobial peptides, a cationic antimicrobial peptide SAEP-4 with vancomycin-independent activity [17,24] was used as a control. Similarly, the SAEP-4 was incubated with S. aureus in the presence or absence of vancomycin.…”

“…Concentrations of nisin Z were determined based on HPLC peak area. As a control, a cationic antimicrobial peptide (SAEP-4: KFFKFFKFF) [16,17] was synthesised as described previously [18].…”