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

Mei-Ling Han, Yan Zhu, Darren J. Creek, Yu-Wei Lin, Dovile Anderson, Hsin-Hui Shen, Brian Tsuji, Alina D. Gutu, Samuel M. Moskowitz, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere02656-17
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Glycerophospholipids
  • L-Ara4N biosynthesis
  • Lipid A modification
  • Metabolomics
  • Methionine salvage cycle
  • Polymyxin resistance
  • Pseudomonas aeruginosa

Cite this

@article{5037ee3301af49638c3f3d79b92e4c58,
title = "Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa",
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 = "Glycerophospholipids, L-Ara4N biosynthesis, Lipid A modification, Metabolomics, Methionine salvage cycle, Polymyxin resistance, Pseudomonas aeruginosa",
author = "Mei-Ling Han and Yan Zhu and Creek, {Darren J.} and Yu-Wei Lin and Dovile Anderson and Hsin-Hui Shen and Brian Tsuji and Gutu, {Alina D.} and Moskowitz, {Samuel M.} and Tony Velkov and Jian Li",
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language = "English",
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journal = "Antimicrobial Agents and Chemotherapy",
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Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa. / Han, Mei-Ling; Zhu, Yan; Creek, Darren J.; Lin, Yu-Wei; Anderson, Dovile; Shen, Hsin-Hui; Tsuji, Brian; Gutu, Alina D.; Moskowitz, Samuel M.; Velkov, Tony; Li, Jian.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 6, e02656-17, 01.06.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa

AU - Han, Mei-Ling

AU - Zhu, Yan

AU - Creek, Darren J.

AU - Lin, Yu-Wei

AU - Anderson, Dovile

AU - Shen, Hsin-Hui

AU - Tsuji, Brian

AU - Gutu, Alina D.

AU - Moskowitz, Samuel M.

AU - Velkov, Tony

AU - Li, Jian

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

KW - Glycerophospholipids

KW - L-Ara4N biosynthesis

KW - Lipid A modification

KW - Metabolomics

KW - Methionine salvage cycle

KW - Polymyxin resistance

KW - Pseudomonas aeruginosa

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U2 - 10.1128/AAC.02656-17

DO - 10.1128/AAC.02656-17

M3 - Article

VL - 62

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

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