Metabolomic analysis uncovered the synergistic mechanisms of polymyxin B in combination with rifampicin against MDR <em>Acinetobacter baumannii</em> — ASN Events
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  3. Metabolomic analysis uncovered the synergistic mechanisms of polymyxin B in combination with rifampicin against MDR Acinetobacter baumannii

Metabolomic analysis uncovered the synergistic mechanisms of polymyxin B in combination with rifampicin against MDR Acinetobacter baumannii (#402)

Jinxin Zhao 1 , Yu-Wei Lin 1 , Meiling Han 1 , Darren Creek 2 , Tony Velkov 3 , Yan Zhu 1 , Jian Li 1
  1. Department of Microbiology, Monash University, Melbourne, VIC, Australia
  2. Drug Delivery, Disposition and Dynamics, Monash University, Melbourne, VIC, Australia
  3. Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia

Background:

Polymyxins are currently used as the last-line therapy against multidrug-resistant (MDR) Acinetobacter baumannii. As resistance to polymyxins can emerge in A. baumannii with monotherapy, combination therapies are often employed in the clinic. Previous studies showed that polymyxin-rifampicin combination displayed synergistic killing against MDR A. baumannii; however, the synergistic mechanism remains unclear. In the present study, we employed metabolomics to investigate the synergistic mechanisms of polymyxin B-rifampicin combination against a model strain of MDR A. baumannii AB5075.

 

Methods:

Bacterial log-phase culture was treated with polymyxin B (0.75 mg/L), rifampicin (1 mg/L), and their combination, respectively. Samples were collected at 0, 1, 4 and 24 hr, and LC-MS was employed to analyse the metabolome. MzMatch, IDEOM and MetaboAnalyst were used for bioinformatic analysis. Metabolites with fold change > 2, FDR < 0.05 were subjected to pathway analysis.

 

Results:

Polymyxin B monotherapy only caused early (1 hr) perturbation of Phosphatidylethanolamines metabolism (e.g. sn-glycero-3-phosphoethanolamine). Rifampicin monotherapy induced significant perturbations in nucleotide and amino acid metabolism (14 metabolites) at 4 hr. More key metabolic pathways (e.g. energy, lipid, nucleotide, amino acid metabolism) were significantly perturbed by the combination at 1 and 4 hr (36 and 61 significant metabolites, respectively). Significant changes in the levels of glycerophospholipids and fatty acids were observed after the combination treatment for 1 and 4 hr. Of particularly interested is that the combination exclusively increased the intermediate metabolite pools in pentose phosphate pathway at 1 hr. Furthermore, the pyrimidine metabolism and histidine degradation pathways were significantly increased. Interestingly, metabolites in the nucleotide and amino acid biosynthesis pathways were significantly decreased at 4 hr. Compared to each monotherapy, most key metabolic pathways were disrupted by this combination.

 

Conclusions:

This is the first study to employ metabolomics to unveil the synergistic killing mechanisms by polymyxin-rifampicin combination against MDR A. baumannii. The time-dependent synergistic activity via disruption of PPP, nucleotide and amino acid metabolism will help design better polymyxin combinations in the clinic.

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