Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii
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 un...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2018-11-01
|
Series: | Frontiers in Microbiology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2018.02776/full |
id |
doaj-1de38cd028744f2388e0132342191aea |
---|---|
record_format |
Article |
spelling |
doaj-1de38cd028744f2388e0132342191aea2020-11-24T23:58:02ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-11-01910.3389/fmicb.2018.02776422854Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumanniiMei-Ling Han0Mei-Ling Han1Xiaofen Liu2Tony Velkov3Yu-Wei Lin4Yan Zhu5Mengyao Li6Heidi H. Yu7Zhihui Zhou8Darren J. Creek9Jing Zhang10Jian Li11Jian Li12Biomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaDepartment of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, AustraliaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaBiomedicine Discovery Institute, Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, VIC, AustraliaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaBackground: 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.https://www.frontiersin.org/article/10.3389/fmicb.2018.02776/fullpolymyxinbeta-lactamcombination therapylipopolysaccharidepeptidoglycanmetabolomics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mei-Ling Han Mei-Ling Han Xiaofen Liu Tony Velkov Yu-Wei Lin Yan Zhu Mengyao Li Heidi H. Yu Zhihui Zhou Darren J. Creek Jing Zhang Jian Li Jian Li |
spellingShingle |
Mei-Ling Han Mei-Ling Han Xiaofen Liu Tony Velkov Yu-Wei Lin Yan Zhu Mengyao Li Heidi H. Yu Zhihui Zhou Darren J. Creek Jing Zhang Jian Li Jian Li Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii Frontiers in Microbiology polymyxin beta-lactam combination therapy lipopolysaccharide peptidoglycan metabolomics |
author_facet |
Mei-Ling Han Mei-Ling Han Xiaofen Liu Tony Velkov Yu-Wei Lin Yan Zhu Mengyao Li Heidi H. Yu Zhihui Zhou Darren J. Creek Jing Zhang Jian Li Jian Li |
author_sort |
Mei-Ling Han |
title |
Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii |
title_short |
Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii |
title_full |
Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii |
title_fullStr |
Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii |
title_full_unstemmed |
Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii |
title_sort |
metabolic analyses revealed time-dependent synergistic killing by colistin and aztreonam combination against multidrug-resistant acinetobacter baumannii |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2018-11-01 |
description |
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. |
topic |
polymyxin beta-lactam combination therapy lipopolysaccharide peptidoglycan metabolomics |
url |
https://www.frontiersin.org/article/10.3389/fmicb.2018.02776/full |
work_keys_str_mv |
AT meilinghan metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT meilinghan metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT xiaofenliu metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT tonyvelkov metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT yuweilin metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT yanzhu metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT mengyaoli metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT heidihyu metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT zhihuizhou metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT darrenjcreek metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT jingzhang metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT jianli metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii AT jianli metabolicanalysesrevealedtimedependentsynergistickillingbycolistinandaztreonamcombinationagainstmultidrugresistantacinetobacterbaumannii |
_version_ |
1725452198535495680 |