Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa.

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