Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii.
Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survival of infected G. mellonella was significantly higher when treated with polymyxin B and netropsin in combination than when treated with polymyxin B or netropsin alone. We propose a netropsin combination therapy that minimises the use of polymyxin B when treating infections with multidrug resistant Gram-negative bacteria.
Super-bacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.|University of Science and Technology, Daejeon 34113, South Korea.
Joon-Hui
JH
Chung
Super-bacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.
Abhayprasad
A
Bhat
University of Science and Technology, Daejeon 34113, South Korea.|Industrial Bio-materials Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.
Chang-Jin
CJ
Kim
Department of Laboratory Medicine and Research Institute of Antimicrobial Resistance, Yonsei University College of Medicine, Seoul 03722, South Korea.
Dongeun
D
Yong
Super-bacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.|University of Science and Technology, Daejeon 34113, South Korea.
Choong-Min
CM
Ryu
D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000302:isolation & purification; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D023421:Models, Animal; D009036:Moths / Q000382:microbiology*; D009429:Netropsin / Q000627:therapeutic use*; D011112:Polymyxin B / Q000627:therapeutic use*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects; D012763:Shigella flexneri / Q000187:drug effects
D000900:Anti-Bacterial Agents; D009429:Netropsin; D011112:Polymyxin B