Mechanistic insights from global metabolomics studies into synergistic bactericidal effect of a polymyxin B combination with tamoxifen against cystic fibrosis MDR Pseudomonas aeruginosa

Publication date: Available online 10 November 2018Source: Computational and Structural Biotechnology JournalAuthor(s): Maytham Hussein, Mei-Ling Han, Yan Zhu, Elena K. Schneider-Futschik, Xiaohan Hu, Qi Tony Zhou, Yu-Wei Lin, Dovile Anderson, Darren J. Creek, Daniel Hoyer, Jian Li, Tony VelkovAbstractPolymyxins are amongst the most important antibiotics in modern medicine, in recent times their clinical utility has been overshadowed by nosocomial outbreaks of polymyxin resistant MDR Gram-negative ‘superbugs’. An effective strategy to surmount polymyxin resistance is combination therapy with FDA-approved non-antibiotic drugs. Herein we used untargeted metabolomics to investigate the mechanism(s) of synergy between polymyxin B and the selective estrogen receptor modulator (SERM) tamoxifen against a polymyxin-resistant MDR cystic fibrosis (CF) Pseudomonas aeruginosa FADDI-PA006 isolate (polymyxin B MIC = 8 mg/L, it is an MDR polymyxin resistant P. aeruginosa isolated from the lungs of a CF patient). The metabolome of FADDI-PA006 was profiled at 15 min, 1 and 4 h following treatment with polymyxin B (2 mg/L), tamoxifen (8 mg/L) either as monotherapy or in combination. At 15 min, the combination treatment induced a marked decrease in lipids, primarily fatty acid and glycerophospholipid metabolites that are involved in the biosynthesis of bacterial membranes. In line with the polymyxin-resistant status of this strain, at 1 h, both polymyxin B and tamoxifen mo...
Source: Computational and Structural Biotechnology Journal - Category: Biotechnology Source Type: research