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

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

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Abstract

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.

Item Type:	Article (Journal)
Additional Information:	8219/65379
Uncontrolled Keywords:	Acinetobacter baumannii, colistin/doripenem combination, antibiotic
Subjects:	Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology R Medicine > RM Therapeutics. Pharmacology > RM300 Drugs and their action
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	International Institute for Halal Research and Training (INHART)
Depositing User:	Dr Mohd Hafidz Mahamad Maifiah
Date Deposited:	12 Sep 2018 16:22
Last Modified:	12 Sep 2018 16:22
URI:	http://irep.iium.edu.my/id/eprint/65379

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