Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

Combination therapy is deployed for the treatment of multidrug-resistant Acinetobacter baumannii, as it can rapidly develop resistance to current antibiotics. This is the first study to investigate the synergistic effect of colistin/doripenem combination on the metabolome of A. baumannii. The met...

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Main Authors:	Mahamad Maifiah, Mohd Hafidz, Creek, Darren J., Nation, Roger L., Forrest, Alan, Tsuji, Brian T., Velkov, Tony, Li, Jian
Format:	Article
Language:	English English
Published:	Springer Nature Limited. 2017
Subjects:	QR Microbiology RM Therapeutics. Pharmacology RM300 Drugs and their action
Online Access:	http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/7/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible.pdf http://irep.iium.edu.my/65379/8/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible%20SCOPUS.pdf

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spelling	iium-653792018-09-12T08:22:55Z http://irep.iium.edu.my/65379/ Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii Mahamad Maifiah, Mohd Hafidz Creek, Darren J. Nation, Roger L. Forrest, Alan Tsuji, Brian T. Velkov, Tony Li, Jian QR Microbiology RM Therapeutics. Pharmacology RM300 Drugs and their action Combination therapy is deployed for the treatment of multidrug-resistant Acinetobacter baumannii, as it can rapidly develop resistance to current antibiotics. This is the first study to investigate the synergistic effect of colistin/doripenem combination on the metabolome of A. baumannii. The metabolite levels were measured using LC-MS following treatment with colistin (2 mg/L) or doripenem (25 mg/L) alone, and their combination at 15 min, 1 hr and 4 hr (n = 4). Colistin caused early (15 min and 1 hr) disruption of the bacterial outer membrane and cell wall, as demonstrated by perturbation of glycerophospholipids and fatty acids. Concentrations of peptidoglycan biosynthesis metabolites decreased at 4 hr by doripenem alone, reflecting its mechanism of action. The combination induced significant changes to more key metabolic pathways relative to either monotherapy. Down-regulation of cell wall biosynthesis (via D-sedoheptulose 7-phosphate) and nucleotide metabolism (via D-ribose 5-phosphate) was associated with perturbations in the pentose phosphate pathway induced initially by colistin (15 min and 1 hr) and later by doripenem (4 hr). We discovered that the combination synergistically killed A. baumannii via time-dependent inhibition of different key metabolic pathways. Our study highlights the significant potential of systems pharmacology in elucidating the mechanism of synergy and optimizing antibiotic pharmacokinetics/pharmacodynamics. Springer Nature Limited. 2017-03-30 Article PeerReviewed application/pdf en http://irep.iium.edu.my/65379/7/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible.pdf application/pdf en http://irep.iium.edu.my/65379/8/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible%20SCOPUS.pdf Mahamad Maifiah, Mohd Hafidz and Creek, Darren J. and Nation, Roger L. and Forrest, Alan and Tsuji, Brian T. and Velkov, Tony and Li, Jian (2017) Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii. Scientific Reports, 7. pp. 1-12. ISSN 2045-2322 https://www.nature.com/articles/srep45527.pdf 10.1038/srep45527
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 RM Therapeutics. Pharmacology RM300 Drugs and their action
spellingShingle	QR Microbiology RM Therapeutics. Pharmacology RM300 Drugs and their action Mahamad Maifiah, Mohd Hafidz Creek, Darren J. Nation, Roger L. Forrest, Alan Tsuji, Brian T. Velkov, Tony Li, Jian Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
description	Combination therapy is deployed for the treatment of multidrug-resistant Acinetobacter baumannii, as it can rapidly develop resistance to current antibiotics. This is the first study to investigate the synergistic effect of colistin/doripenem combination on the metabolome of A. baumannii. The metabolite levels were measured using LC-MS following treatment with colistin (2 mg/L) or doripenem (25 mg/L) alone, and their combination at 15 min, 1 hr and 4 hr (n = 4). Colistin caused early (15 min and 1 hr) disruption of the bacterial outer membrane and cell wall, as demonstrated by perturbation of glycerophospholipids and fatty acids. Concentrations of peptidoglycan biosynthesis metabolites decreased at 4 hr by doripenem alone, reflecting its mechanism of action. The combination induced significant changes to more key metabolic pathways relative to either monotherapy. Down-regulation of cell wall biosynthesis (via D-sedoheptulose 7-phosphate) and nucleotide metabolism (via D-ribose 5-phosphate) was associated with perturbations in the pentose phosphate pathway induced initially by colistin (15 min and 1 hr) and later by doripenem (4 hr). We discovered that the combination synergistically killed A. baumannii via time-dependent inhibition of different key metabolic pathways. Our study highlights the significant potential of systems pharmacology in elucidating the mechanism of synergy and optimizing antibiotic pharmacokinetics/pharmacodynamics.
format	Article
author	Mahamad Maifiah, Mohd Hafidz Creek, Darren J. Nation, Roger L. Forrest, Alan Tsuji, Brian T. Velkov, Tony Li, Jian
author_facet	Mahamad Maifiah, Mohd Hafidz Creek, Darren J. Nation, Roger L. Forrest, Alan Tsuji, Brian T. Velkov, Tony Li, Jian
author_sort	Mahamad Maifiah, Mohd Hafidz
title	Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
title_short	Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
title_full	Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
title_fullStr	Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
title_full_unstemmed	Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii
title_sort	untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against acinetobacter baumannii
publisher	Springer Nature Limited.
publishDate	2017
url	http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/ http://irep.iium.edu.my/65379/7/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible.pdf http://irep.iium.edu.my/65379/8/65379%20Untargeted%20metabolomics%20analysis%20reveals%20key%20pathways%20responsible%20SCOPUS.pdf
first_indexed	2023-09-18T21:32:46Z
last_indexed	2023-09-18T21:32:46Z
_version_	1777412620992643072

Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

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