Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

Mei-Ling Han, Xiaofeng Liu, Tony Velkov, Yu-Wei Lin, Yan Zhu, Mengyao Li, Heidi H. Yu, Zhihui Zhou, Darren J. Creek, Jing Zhang, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance. Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis. Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations. Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

Original languageEnglish
Article number2776
Number of pages12
JournalFrontiers in Microbiology
Volume9
DOIs
Publication statusPublished - 16 Nov 2018

Keywords

  • Polymyxin beta-lactam combination therapy lipopolysaccharide peptidoglycan metabolomics

Cite this

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title = "Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii",
abstract = "Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance. Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis. Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations. Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.",
keywords = "Polymyxin beta-lactam combination therapy lipopolysaccharide peptidoglycan metabolomics",
author = "Mei-Ling Han and Xiaofeng Liu and Tony Velkov and Yu-Wei Lin and Yan Zhu and Mengyao Li and Yu, {Heidi H.} and Zhihui Zhou and Creek, {Darren J.} and Jing Zhang and Jian Li",
year = "2018",
month = "11",
day = "16",
doi = "10.3389/fmicb.2018.02776",
language = "English",
volume = "9",
journal = "Frontiers in Microbiology",
issn = "1664-302X",
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Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii. / Han, Mei-Ling; Liu, Xiaofeng; Velkov, Tony; Lin, Yu-Wei; Zhu, Yan; Li, Mengyao; Yu, Heidi H.; Zhou, Zhihui; Creek, Darren J.; Zhang, Jing; Li, Jian.

In: Frontiers in Microbiology, Vol. 9, 2776, 16.11.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii

AU - Han, Mei-Ling

AU - Liu, Xiaofeng

AU - Velkov, Tony

AU - Lin, Yu-Wei

AU - Zhu, Yan

AU - Li, Mengyao

AU - Yu, Heidi H.

AU - Zhou, Zhihui

AU - Creek, Darren J.

AU - Zhang, Jing

AU - Li, Jian

PY - 2018/11/16

Y1 - 2018/11/16

N2 - Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance. Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis. Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations. Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

AB - Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance. Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis. Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations. Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

KW - Polymyxin beta-lactam combination therapy lipopolysaccharide peptidoglycan metabolomics

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U2 - 10.3389/fmicb.2018.02776

DO - 10.3389/fmicb.2018.02776

M3 - Article

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

SN - 1664-302X

M1 - 2776

ER -