Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination With Tamoxifen Against Cystic Fibrosis MDR Pseudomonas aeruginosa

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 Velkov

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymyxins 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 monotherapies produced little effect on bacterial metabolism. In contrast to the combination which induced extensive reduction (≥ 1.0-log2-fold, p ≤ 0.05; FDR ≤ 0.05) in the levels of essential intermediates involved in cell envelope biosynthesis. Overall, these novel findings demonstrate that the primary mechanisms underlying the synergistic bactericidal effect of the combination against the polymyxin-resistant P. aeruginosa CF isolate FADDI-PA006 involves a disruption of the cell envelope biogenesis and an inhibition of aminoarabinose LPS modifications that confer polymyxin resistance.

Original languageEnglish
Pages (from-to)587-599
Number of pages13
JournalComputational and Structural Biotechnology Journal
Volume16
DOIs
Publication statusPublished - 1 Jan 2018

Cite this

@article{48dee0a30c3944889926cf7e3702f783,
title = "Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination With Tamoxifen Against Cystic Fibrosis MDR Pseudomonas aeruginosa",
abstract = "Polymyxins 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 monotherapies produced little effect on bacterial metabolism. In contrast to the combination which induced extensive reduction (≥ 1.0-log2-fold, p ≤ 0.05; FDR ≤ 0.05) in the levels of essential intermediates involved in cell envelope biosynthesis. Overall, these novel findings demonstrate that the primary mechanisms underlying the synergistic bactericidal effect of the combination against the polymyxin-resistant P. aeruginosa CF isolate FADDI-PA006 involves a disruption of the cell envelope biogenesis and an inhibition of aminoarabinose LPS modifications that confer polymyxin resistance.",
author = "Maytham Hussein and Mei-Ling Han and Yan Zhu and Schneider-Futschik, {Elena K.} and Xiaohan Hu and Zhou, {Qi Tony} and Yu-Wei Lin and Dovile Anderson and Creek, {Darren J.} and Daniel Hoyer and Jian Li and Tony Velkov",
year = "2018",
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day = "1",
doi = "10.1016/j.csbj.2018.11.001",
language = "English",
volume = "16",
pages = "587--599",
journal = "Computational and Structural Biotechnology Journal",
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Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination With Tamoxifen Against Cystic Fibrosis MDR Pseudomonas aeruginosa. / Hussein, Maytham; Han, Mei-Ling; Zhu, Yan; Schneider-Futschik, Elena K.; Hu, Xiaohan; Zhou, Qi Tony; Lin, Yu-Wei; Anderson, Dovile; Creek, Darren J.; Hoyer, Daniel; Li, Jian; Velkov, Tony.

In: Computational and Structural Biotechnology Journal, Vol. 16, 01.01.2018, p. 587-599.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination With Tamoxifen Against Cystic Fibrosis MDR Pseudomonas aeruginosa

AU - Hussein, Maytham

AU - Han, Mei-Ling

AU - Zhu, Yan

AU - Schneider-Futschik, Elena K.

AU - Hu, Xiaohan

AU - Zhou, Qi Tony

AU - Lin, Yu-Wei

AU - Anderson, Dovile

AU - Creek, Darren J.

AU - Hoyer, Daniel

AU - Li, Jian

AU - Velkov, Tony

PY - 2018/1/1

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