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Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling

Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a very problematic pathogen over the past decades, with a high incidence in nosocomial infections. Discovered in the late 1940s but abandoned in the 1970s, polymyxins (i.e., polymyxin B and colistin) have been revived as the last-line...

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Autores principales: Zhu, Yan, Zhao, Jinxin, Maifiah, Mohd Hafidz Mahamad, Velkov, Tony, Schreiber, Falk, Li, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365644/
https://www.ncbi.nlm.nih.gov/pubmed/30746493
http://dx.doi.org/10.1128/mSystems.00157-18
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author Zhu, Yan
Zhao, Jinxin
Maifiah, Mohd Hafidz Mahamad
Velkov, Tony
Schreiber, Falk
Li, Jian
author_facet Zhu, Yan
Zhao, Jinxin
Maifiah, Mohd Hafidz Mahamad
Velkov, Tony
Schreiber, Falk
Li, Jian
author_sort Zhu, Yan
collection PubMed
description Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a very problematic pathogen over the past decades, with a high incidence in nosocomial infections. Discovered in the late 1940s but abandoned in the 1970s, polymyxins (i.e., polymyxin B and colistin) have been revived as the last-line therapy against Gram-negative “superbugs,” including MDR A. baumannii. Worryingly, resistance to polymyxins in A. baumannii has been increasingly reported, urging the development of novel antimicrobial therapies to rescue this last-line class of antibiotics. In the present study, we integrated genome-scale metabolic modeling with multiomics data to elucidate the mechanisms of cellular responses to colistin treatment in A. baumannii. A genome-scale metabolic model, iATCC19606, was constructed for strain ATCC 19606 based on the literature and genome annotation, containing 897 genes, 1,270 reactions, and 1,180 metabolites. After extensive curation, prediction of growth on 190 carbon sources using iATCC19606 achieved an overall accuracy of 84.3% compared to Biolog experimental results. Prediction of gene essentiality reached a high accuracy of 86.1% and 82.7% compared to two transposon mutant libraries of AB5075 and ATCC 17978, respectively. Further integrative modeling with our correlative transcriptomics and metabolomics data deciphered the complex regulation on metabolic responses to colistin treatment, including (i) upregulated fluxes through gluconeogenesis, the pentose phosphate pathway, and amino acid and nucleotide biosynthesis; (ii) downregulated TCA cycle and peptidoglycan and lipopolysaccharide biogenesis; and (iii) altered fluxes over respiratory chain. Our results elucidated the interplay of multiple metabolic pathways under colistin treatment in A. baumannii and provide key mechanistic insights into optimizing polymyxin combination therapy. IMPORTANCE Combating antimicrobial resistance has been highlighted as a critical global health priority. Due to the drying drug discovery pipeline, polymyxins have been employed as the last-line therapy against Gram-negative “superbugs”; however, the detailed mechanisms of antibacterial killing remain largely unclear, hampering the improvement of polymyxin therapy. Our integrative modeling using the constructed genome-scale metabolic model iATCC19606 and the correlative multiomics data provide the fundamental understanding of the complex metabolic responses to polymyxin treatment in A. baumannii at the systems level. The model iATCC19606 may have a significant potential in antimicrobial systems pharmacology research in A. baumannii.
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spelling pubmed-63656442019-02-11 Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling Zhu, Yan Zhao, Jinxin Maifiah, Mohd Hafidz Mahamad Velkov, Tony Schreiber, Falk Li, Jian mSystems Research Article Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a very problematic pathogen over the past decades, with a high incidence in nosocomial infections. Discovered in the late 1940s but abandoned in the 1970s, polymyxins (i.e., polymyxin B and colistin) have been revived as the last-line therapy against Gram-negative “superbugs,” including MDR A. baumannii. Worryingly, resistance to polymyxins in A. baumannii has been increasingly reported, urging the development of novel antimicrobial therapies to rescue this last-line class of antibiotics. In the present study, we integrated genome-scale metabolic modeling with multiomics data to elucidate the mechanisms of cellular responses to colistin treatment in A. baumannii. A genome-scale metabolic model, iATCC19606, was constructed for strain ATCC 19606 based on the literature and genome annotation, containing 897 genes, 1,270 reactions, and 1,180 metabolites. After extensive curation, prediction of growth on 190 carbon sources using iATCC19606 achieved an overall accuracy of 84.3% compared to Biolog experimental results. Prediction of gene essentiality reached a high accuracy of 86.1% and 82.7% compared to two transposon mutant libraries of AB5075 and ATCC 17978, respectively. Further integrative modeling with our correlative transcriptomics and metabolomics data deciphered the complex regulation on metabolic responses to colistin treatment, including (i) upregulated fluxes through gluconeogenesis, the pentose phosphate pathway, and amino acid and nucleotide biosynthesis; (ii) downregulated TCA cycle and peptidoglycan and lipopolysaccharide biogenesis; and (iii) altered fluxes over respiratory chain. Our results elucidated the interplay of multiple metabolic pathways under colistin treatment in A. baumannii and provide key mechanistic insights into optimizing polymyxin combination therapy. IMPORTANCE Combating antimicrobial resistance has been highlighted as a critical global health priority. Due to the drying drug discovery pipeline, polymyxins have been employed as the last-line therapy against Gram-negative “superbugs”; however, the detailed mechanisms of antibacterial killing remain largely unclear, hampering the improvement of polymyxin therapy. Our integrative modeling using the constructed genome-scale metabolic model iATCC19606 and the correlative multiomics data provide the fundamental understanding of the complex metabolic responses to polymyxin treatment in A. baumannii at the systems level. The model iATCC19606 may have a significant potential in antimicrobial systems pharmacology research in A. baumannii. American Society for Microbiology 2019-02-05 /pmc/articles/PMC6365644/ /pubmed/30746493 http://dx.doi.org/10.1128/mSystems.00157-18 Text en Copyright © 2019 Zhu et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhu, Yan
Zhao, Jinxin
Maifiah, Mohd Hafidz Mahamad
Velkov, Tony
Schreiber, Falk
Li, Jian
Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_full Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_fullStr Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_full_unstemmed Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_short Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_sort metabolic responses to polymyxin treatment in acinetobacter baumannii atcc 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365644/
https://www.ncbi.nlm.nih.gov/pubmed/30746493
http://dx.doi.org/10.1128/mSystems.00157-18
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