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

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.

Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa

“…The increased permeability of the outer membrane is supported by our fractional inhibitory concentration results (Tables S5 to S7), in which the enrofloxacin MICs decreased in the presence of polymyxin B and vice versa. Additionally, the mechanistic data from polymyxin-doripenem combination against A. baumannii also showed a similar mechanism of synergy (56). The exclusion of either aspect of the synergy mechanism from the MBM resulted in a model that could not be estimated, as the simplified model provided poor curve fits (R 2 of Ͻ0.50; data not shown).…”

Dose Optimization of Colistin Combinations against Carbapenem-Resistant Acinetobacter baumannii from Patients with Hospital-Acquired Pneumonia in China by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

“…Colistin kills bacteria by membrane disruption which simultaneously increases meropenem entrance into bacteria (17). It had been reported that the synergy of colistin and carbapenems (doripenem) was time-dependent inhibition of different metabolic pathways in a metabolomics study (18). Colistin induced disruption of bacterial lipids and metabolic changes via pentose phosphate pathway metabolism in early stages.…”

The Future of Metabolomics and Individual Monitoring in Antimicrobial Therapy

“…In this order of ideas metabolomics can be an important strategy for elucidate the synergistic metabolic pathways that can be selected as antimicrobial targets and optimizing antibiotic pharmacokinetics/ pharmacodynamics that avoid resistance emergence [11].…”