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Antimicrob Agents Chemother. 2018 May 25;62(6). pii: e02656-17. doi: 10.1128/AAC.02656-17. Print 2018 Jun.

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

Author information

1
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
2
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
3
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
4
Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Clayton, Victoria, Australia.
5
Department of Pharmacy Practice, University at Buffalo, Buffalo, New York, USA.
6
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
7
Vertex Pharmaceuticals, Boston, Massachusetts, USA.
8
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia Tony.Velkov@unimelb.edu.au Jian.Li@monash.edu.
9
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.
10
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia Tony.Velkov@unimelb.edu.au Jian.Li@monash.edu.

Abstract

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 P. aeruginosa strain K ([PAK] polymyxin B MIC, 1 mg/liter) and its paired pmrB mutant strains, PAKpmrB6 and PAKpmrB12 (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. PAKpmrB6 and PAKpmrB12, 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 speE (encoding spermidine synthase) in PAKpmrB6, and metabolomics data revealed a decreased intracellular level of spermidine in PAKpmrB6 compared to that in 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 those in the wild-type PAK. Moreover, the more resistant PAKpmrB12 mutant exhibited much lower levels of phospholipids than the PAKpmrB6 mutant, suggesting that 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.

KEYWORDS:

Pseudomonas aeruginosa; glycerophospholipids; l-Ara4N biosynthesis; lipid A modification; metabolomics; methionine salvage cycle; polymyxin resistance

PMID:
29632014
PMCID:
PMC5971563
DOI:
10.1128/AAC.02656-17
[Indexed for MEDLINE]
Free PMC Article

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