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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Main Authors:	Zhu, Yan, Zhao, Jinxin, Mahamad Maifiah, Mohd Hafidz, Velkov, Tony, Schreiber, Falk, Lia, Jian
Format:	Article
Language:	English English
Published:	American Society for Microbiology 2019
Subjects:	QR Microbiology RM300 Drugs and their action
Online Access:	http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/7/70940_Metabolic%20Responses%20to%20Polymyxin_wos.pdf http://irep.iium.edu.my/70940/13/70940_%20Metabolic%20responses%20to%20polymyxin%20treatment%20in%20acinetobacter%20baumannii%20ATCC%2019606.pdf

id	iium-70940
recordtype	eprints
spelling	iium-709402020-01-23T08:42:43Z http://irep.iium.edu.my/70940/ Metabolic responses to polymyxin treatment in acinetobacter baumannii ATCC 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling Zhu, Yan Zhao, Jinxin Mahamad Maifiah, Mohd Hafidz Velkov, Tony Schreiber, Falk Lia, Jian QR Microbiology RM300 Drugs and their action 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. American Society for Microbiology 2019 Article PeerReviewed application/pdf en http://irep.iium.edu.my/70940/7/70940_Metabolic%20Responses%20to%20Polymyxin_wos.pdf application/pdf en http://irep.iium.edu.my/70940/13/70940_%20Metabolic%20responses%20to%20polymyxin%20treatment%20in%20acinetobacter%20baumannii%20ATCC%2019606.pdf Zhu, Yan and Zhao, Jinxin and Mahamad Maifiah, Mohd Hafidz and Velkov, Tony and Schreiber, Falk and Lia, Jian (2019) Metabolic responses to polymyxin treatment in acinetobacter baumannii ATCC 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling. MSYSTEMS, 4 (1). pp. 1-15. ISSN 2379-5077 https://msystems.asm.org/content/msys/4/1/e00157-18.full.pdf 10.1128/mSystems.00157-18
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English English
topic	QR Microbiology RM300 Drugs and their action
spellingShingle	QR Microbiology RM300 Drugs and their action Zhu, Yan Zhao, Jinxin Mahamad Maifiah, Mohd Hafidz Velkov, Tony Schreiber, Falk Lia, Jian Metabolic responses to polymyxin treatment in acinetobacter baumannii ATCC 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling
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.
format	Article
author	Zhu, Yan Zhao, Jinxin Mahamad Maifiah, Mohd Hafidz Velkov, Tony Schreiber, Falk Lia, Jian
author_facet	Zhu, Yan Zhao, Jinxin Mahamad Maifiah, Mohd Hafidz Velkov, Tony Schreiber, Falk Lia, Jian
author_sort	Zhu, Yan
title	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_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_sort	metabolic responses to polymyxin treatment in acinetobacter baumannii atcc 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling
publisher	American Society for Microbiology
publishDate	2019
url	http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/7/70940_Metabolic%20Responses%20to%20Polymyxin_wos.pdf http://irep.iium.edu.my/70940/13/70940_%20Metabolic%20responses%20to%20polymyxin%20treatment%20in%20acinetobacter%20baumannii%20ATCC%2019606.pdf
first_indexed	2023-09-18T21:40:42Z
last_indexed	2023-09-18T21:40:42Z
_version_	1777413119961726976

Metabolic responses to polymyxin treatment in acinetobacter baumannii ATCC 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling

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