Alterations of metabolic and lipid profiles in polymyxin-resistant Pseudomonas aeruginosa [PublishAheadOfPrint]

Multidrug-resistant Pseudomonas aeruginosa presents a global medical challenge and polymyxins are a key last-resort therapeutic option. Unfortunately, polymyxin resistance in P. aeruginosa has been increasingly reported. The present study was designed to define metabolic differences between paired polymyxin-susceptible and -resistant P. aeruginosa strains using untargeted metabolomics and lipidomics analyses. The metabolomes of wild-type PAK (polymyxin B MIC 1 mg/L) and its paired pmrB mutant strains, PAKpmrB6 and PAKpmrB12 (polymyxin B MICs 16 mg/L and 64 mg/L, respectively) were characterized using liquid chromatography-mass spectrometry, and metabolic differences were identified through multivariate and univariate statistics. PAKpmrB6 and PAKpmrB12 which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose showed significant perturbations in amino acid and carbohydrate metabolism, particularly intermediate metabolites from 4-amino-4-deoxy-L-arabinose synthesis and the methionine salvage cycle pathways. Genomics result showed a premature termination (Y275stop) in speE (encoding spermidine synthase) in PAKpmrB6 and metabolomics data revealed a decreased intracellular level of spermidine in PAKpmrB6 compared to PAKpmrB12. Our results indicate that spermidine may play an important role in high-level polymyxin resistance in P. aeruginosa. Interestingly, both pmrB mutants had decreased levels of phospholipids, fatty acids and acyl-coenzyme A compared to the wild-type PAK strain. Moreover, the more resistant PAKpmrB12 mutant exhibited much lower levels of phospholipids than the PAKpmrB6 mutant, suggesting the decreased phospholipid level was associated with polymyxin resistance. In summary, this study provides novel mechanistic information on polymyxin resistance in P. aeruginosa and highlights its impacts on bacterial metabolism.

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