Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-resistant Pseudomonas aeruginosa

Yu-Wei Lin, Mei-Ling Han, Jinxin Zhao, Yan Zhu, Gauri Rao, Alan Forrest, Jiangning Song, Keith S Kaye, Paul Hertzog, Anthony Purcell, Darren Creek, Tony Qi Zhou, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B–enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B–enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.
Original languageEnglish
Article number1146
Number of pages11
JournalFrontiers in Pharmacology
Volume10
DOIs
Publication statusPublished - 3 Oct 2019

Cite this

@article{cc9d010bd3e04f9d846410c6c4803276,
title = "Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-resistant Pseudomonas aeruginosa",
abstract = "Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B–enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B–enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.",
author = "Yu-Wei Lin and Mei-Ling Han and Jinxin Zhao and Yan Zhu and Gauri Rao and Alan Forrest and Jiangning Song and Kaye, {Keith S} and Paul Hertzog and Anthony Purcell and Darren Creek and Zhou, {Tony Qi} and Tony Velkov and Jian Li",
year = "2019",
month = "10",
day = "3",
doi = "10.3389/fphar.2019.01146",
language = "English",
volume = "10",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media",

}

Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-resistant Pseudomonas aeruginosa. / Lin, Yu-Wei; Han, Mei-Ling; Zhao, Jinxin; Zhu, Yan; Rao, Gauri; Forrest, Alan; Song, Jiangning; Kaye, Keith S; Hertzog, Paul; Purcell, Anthony; Creek, Darren; Zhou, Tony Qi; Velkov, Tony; Li, Jian.

In: Frontiers in Pharmacology, Vol. 10, 1146, 03.10.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-resistant Pseudomonas aeruginosa

AU - Lin, Yu-Wei

AU - Han, Mei-Ling

AU - Zhao, Jinxin

AU - Zhu, Yan

AU - Rao, Gauri

AU - Forrest, Alan

AU - Song, Jiangning

AU - Kaye, Keith S

AU - Hertzog, Paul

AU - Purcell, Anthony

AU - Creek, Darren

AU - Zhou, Tony Qi

AU - Velkov, Tony

AU - Li, Jian

PY - 2019/10/3

Y1 - 2019/10/3

N2 - Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B–enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B–enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.

AB - Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B–enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B–enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.

UR - https://www.ncbi.nlm.nih.gov/pubmed/31632279

U2 - 10.3389/fphar.2019.01146

DO - 10.3389/fphar.2019.01146

M3 - Article

VL - 10

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 1146

ER -