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

• Published in: Scientific reports 2017-03, Vol.7 (1), p.45527-45527, Article 45527
• Main Authors: Maifiah, Mohd Hafidz Mahamad, Creek, Darren J., Nation, Roger L., Forrest, Alan, Tsuji, Brian T., Velkov, Tony, Li, Jian
• Format: Article
• Language: English
• Subjects: 631/154/436; 631/553/2710; 692/699/255/1318; Acinetobacter baumannii - drug effects; Acinetobacter baumannii - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotics; Biosynthesis; Cell walls; Colistin; Colistin - pharmacology; D-Ribose; Doripenem - pharmacology; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Fatty acids; Humanities and Social Sciences; Membrane Lipids - metabolism; Metabolic pathways; Metabolism; Metabolites; Metabolomics; multidisciplinary; Multidrug resistance; Pentose phosphate pathway; Peptidoglycans; Pharmacodynamics; Pharmacokinetics; Pharmacology; Ribose; Science; Signal Transduction; Synergistic effect
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep45527

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.