title: Synergistic effect of membrane-active peptides polymyxin B and gramicidin S on multidrug-resistant strains and biofilms of Pseudomonas aeruginosa.
abstract: Multidrug-resistant Pseudomonas aeruginosa is a major cause of severe hospital-acquired infections. Currently, polymyxin B (PMB) is a last-resort antibiotic for the treatment of infections caused by Gram-negative bacteria, despite its undesirable side effects. The delivery of drug combinations has been shown to reduce the required therapeutic doses of antibacterial agents and thereby their toxicity if a synergistic effect is present. In this study, we investigated the synergy between two cyclic antimicrobial peptides, PMB and gramicidin S (GS), against different P. aeruginosa isolates, using a quantitative checkerboard assay with resazurin as a growth indicator. Among the 28 strains that we studied, 20 strains showed a distinct synergistic effect, represented by a fractional inhibitory concentration index (FICI) of ≤0.5. Remarkably, several clinical P. aeruginosa isolates that grew as small-colony variants revealed a nonsynergistic effect, as indicated by FICIs between >0.5 and ≤0.70. In addition to inhibiting the growth of planktonic bacteria, the peptide combinations significantly decreased static biofilm growth compared with treatment with the individual peptides. There was also a faster and more prolonged effect when the combination of PMB and GS was used compared with single-peptide treatments on the metabolic activity of pregrown biofilms. The results of the present study define a synergistic interaction between two cyclic membrane-active peptides toward 17 multidrug-resistant P. aeruginosa and biofilms of P. aeruginosa strain PAO1. Thus, the application of PMB and GS in combination is a promising option for a topical medication and in the prevention of acute and chronic infections caused by multidrug-resistant or biofilm-forming P. aeruginosa.
authors.affiliation: Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Berditsch
authors.affiliation: Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jäger
authors.affiliation: Institute of Functional Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Strempel
authors.affiliation: Institute of Functional Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwartz
authors.affiliation: Institute of Functional Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Overhage
authors.affiliation: Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany Institute of Biological Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany anne.ulrich@kit.edu.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D006096:Gramicidin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin; D011112:Polymyxin B