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Front. Microbiol. | doi: 10.3389/fmicb.2018.02776

Metabolic analyses revealed time-dependent synergistic killing by colistin and aztreonam combination against multidrug-resistant Acinetobacter baumannii

 Mei-Ling Han1,  Xiaofen Liu2, Tony velkov3, Yu-Wei Lin1,  Yan Zhu1,  Mengyao Li1,  Heidi H. Yu1, Zhihui Zhou4,  Darren J. Creek5,  Jing Zhang2* and  Jian Li1
  • 1Department of Microbiology, Monash University, Australia
  • 2Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, China
  • 3Department of Pharmacology & Therapeutics, The University of Melbourne, Australia
  • 4Sir Run Run Shaw Hospital, Zhejiang University, China
  • 5Monash Institute of Pharmaceutical Sciences, Monash University, Parkville campus, Australia

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.
Conclusions: 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

Received: 03 Sep 2018; Accepted: 30 Oct 2018.

Edited by:

Maria A. Mussi, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

Reviewed by:

Ziad Daoud, University of Balamand, Lebanon
Ilya R. Akberdin, Independent researcher  

Copyright: © 2018 Han, Liu, velkov, Lin, Zhu, Li, Yu, Zhou, Creek, Zhang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jing Zhang, Huashan Hospital Affiliated to Fudan University, Institute of Antibiotics, Shanghai, Shanghai Municipality, China,