Comparative metabolomics reveals key pathways associated with the synergistic killing of colistin and sulbactam combination against multidrug-resistant Acinetobacter baumannii

Mei-Ling Han, Xiaofeng Liu, Tony Velkov, Yu-Wei Lin, Yan Zhu, Darren J. Creek, Christopher K. Barlow, Heidi H. Yu, Zhihui Zhou, 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, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii.
Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis.
Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies.
Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.
Original languageEnglish
Article number754
Number of pages11
JournalFrontiers in Pharmacology
Volume10
DOIs
Publication statusPublished - 4 Jul 2019

Keywords

  • polymyxin
  • B-lactam
  • combination therapy
  • lipopolysaccharide
  • peptidoglycan
  • metabolomics

Cite this

@article{2be381f55fe247389758af4c75f69f4e,
title = "Comparative metabolomics reveals key pathways associated with the synergistic killing of colistin and sulbactam 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, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii.Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis.Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies.Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.",
keywords = "polymyxin, B-lactam, combination therapy, lipopolysaccharide, peptidoglycan, metabolomics",
author = "Mei-Ling Han and Xiaofeng Liu and Tony Velkov and Yu-Wei Lin and Yan Zhu and Creek, {Darren J.} and Barlow, {Christopher K.} and Yu, {Heidi H.} and Zhihui Zhou and Jing Zhang and Jian Li",
year = "2019",
month = "7",
day = "4",
doi = "10.3389/fphar.2019.00754",
language = "English",
volume = "10",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media",

}

Comparative metabolomics reveals key pathways associated with the synergistic killing of colistin and sulbactam combination against multidrug-resistant Acinetobacter baumannii. / Han, Mei-Ling; Liu, Xiaofeng; Velkov, Tony; Lin, Yu-Wei; Zhu, Yan; Creek, Darren J.; Barlow, Christopher K.; Yu, Heidi H.; Zhou, Zhihui; Zhang, Jing; Li, Jian.

In: Frontiers in Pharmacology, Vol. 10, 754, 04.07.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Comparative metabolomics reveals key pathways associated with the synergistic killing of colistin and sulbactam combination against multidrug-resistant Acinetobacter baumannii

AU - Han, Mei-Ling

AU - Liu, Xiaofeng

AU - Velkov, Tony

AU - Lin, Yu-Wei

AU - Zhu, Yan

AU - Creek, Darren J.

AU - Barlow, Christopher K.

AU - Yu, Heidi H.

AU - Zhou, Zhihui

AU - Zhang, Jing

AU - Li, Jian

PY - 2019/7/4

Y1 - 2019/7/4

N2 - Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii. However, polymyxin resistance can emerge with monotherapy, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii.Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis.Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies.Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help 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, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii.Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis.Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies.Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.

KW - polymyxin

KW - B-lactam

KW - combination therapy

KW - lipopolysaccharide

KW - peptidoglycan

KW - metabolomics

U2 - 10.3389/fphar.2019.00754

DO - 10.3389/fphar.2019.00754

M3 - Article

VL - 10

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 754

ER -