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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English English |
| Published: |
Springer Nature Limited.
2017
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| Subjects: | |
| 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 |
| Summary: | 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. |
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