Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling

ABSTRACT 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 l...

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Autores principales:	Yan Zhu, Jinxin Zhao, Mohd Hafidz Mahamad Maifiah, Tony Velkov, Falk Schreiber, Jian Li
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Acinetobacter baumannii genome-scale metabolic modeling metabolomics transcriptomics polymyxins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fdb16d4b0c9f48918ae27d415bc17aaf
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spelling	oai:doaj.org-article:fdb16d4b0c9f48918ae27d415bc17aaf2021-12-02T19:46:18ZMetabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling10.1128/mSystems.00157-182379-5077https://doaj.org/article/fdb16d4b0c9f48918ae27d415bc17aaf2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00157-18https://doaj.org/toc/2379-5077ABSTRACT 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.Yan ZhuJinxin ZhaoMohd Hafidz Mahamad MaifiahTony VelkovFalk SchreiberJian LiAmerican Society for MicrobiologyarticleAcinetobacter baumanniigenome-scale metabolic modelingmetabolomicstranscriptomicspolymyxinsMicrobiologyQR1-502ENmSystems, Vol 4, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii genome-scale metabolic modeling metabolomics transcriptomics polymyxins Microbiology QR1-502
spellingShingle	Acinetobacter baumannii genome-scale metabolic modeling metabolomics transcriptomics polymyxins Microbiology QR1-502 Yan Zhu Jinxin Zhao Mohd Hafidz Mahamad Maifiah Tony Velkov Falk Schreiber Jian Li Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
description	ABSTRACT 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.
format	article
author	Yan Zhu Jinxin Zhao Mohd Hafidz Mahamad Maifiah Tony Velkov Falk Schreiber Jian Li
author_facet	Yan Zhu Jinxin Zhao Mohd Hafidz Mahamad Maifiah Tony Velkov Falk Schreiber Jian Li
author_sort	Yan Zhu
title	Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_short	Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_full	Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_fullStr	Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_full_unstemmed	Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling
title_sort	metabolic responses to polymyxin treatment in <italic toggle="yes">acinetobacter baumannii</italic> atcc 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/fdb16d4b0c9f48918ae27d415bc17aaf
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Metabolic Responses to Polymyxin Treatment in <italic toggle="yes">Acinetobacter baumannii</italic> ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling

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