Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

ABSTRACT Polymyxins are a last-line therapy against multidrug-resistant Pseudomonas aeruginosa; however, resistance to polymyxins has been increasingly reported. Therefore, understanding the mechanisms of polymyxin activity and resistance is crucial for preserving their clinical usefulness. This stu...

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Autores principales:	Mei-Ling Han, Yan Zhu, Darren J. Creek, Yu-Wei Lin, Alina D. Gutu, Paul Hertzog, Tony Purcell, Hsin-Hui Shen, Samuel M. Moskowitz, Tony Velkov, Jian Li
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	lipid A modification metabolomics Pseudomonas aeruginosa transcriptomics glycerophospholipids lipopolysaccharide Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0216f278a9a149cba2b98925ca745bbd
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spelling	oai:doaj.org-article:0216f278a9a149cba2b98925ca745bbd2021-12-02T18:39:15ZComparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>10.1128/mSystems.00149-182379-5077https://doaj.org/article/0216f278a9a149cba2b98925ca745bbd2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00149-18https://doaj.org/toc/2379-5077ABSTRACT Polymyxins are a last-line therapy against multidrug-resistant Pseudomonas aeruginosa; however, resistance to polymyxins has been increasingly reported. Therefore, understanding the mechanisms of polymyxin activity and resistance is crucial for preserving their clinical usefulness. This study employed comparative metabolomics and transcriptomics to investigate the responses of polymyxin-susceptible P. aeruginosa PAK (polymyxin B MIC, 1 mg/liter) and its polymyxin-resistant pmrB mutant PAKpmrB6 (MIC, 16 mg/liter) to polymyxin B (4, 8, and 128 mg/liter) at 1, 4, and 24 h, respectively. Our results revealed that polymyxin B at 4 mg/liter induced different metabolic and transcriptomic responses between polymyxin-susceptible and -resistant P. aeruginosa. In strain PAK, polymyxin B significantly activated PmrAB and the mediated arn operon, leading to increased 4-amino-4-deoxy-L-arabinose (L-Ara4N) synthesis and the addition to lipid A. In contrast, polymyxin B did not increase lipid A modification in strain PAKpmrB6. Moreover, the syntheses of lipopolysaccharide and peptidoglycan were significantly decreased in strain PAK but increased in strain PAKpmrB6 due to polymyxin B treatment. In addition, 4 mg/liter polymyxin B significantly perturbed phospholipid and fatty acid levels and induced oxidative stress in strain PAK, but not in PAKpmrB6. Notably, the increased trehalose-6-phosphate levels indicate that polymyxin B potentially caused osmotic imbalance in both strains. Furthermore, 8 and 128 mg/liter polymyxin B significantly elevated lipoamino acid levels and decreased phospholipid levels but without dramatic changes in lipid A modification in wild-type and mutant strains, respectively. Overall, this systems study is the first to elucidate the complex and dynamic interactions of multiple cellular pathways associated with the polymyxin mode of action against P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa has been highlighted by the recent WHO Global Priority Pathogen List due to multidrug resistance. Without new antibiotics, polymyxins remain a last-line therapeutic option for this difficult-to-treat pathogen. The emergence of polymyxin resistance highlights the growing threat to our already very limited antibiotic armamentarium and the urgency to understand the exact mechanisms of polymyxin activity and resistance. Integration of the correlative metabolomics and transcriptomics results in the present study discovered that polymyxin treatment caused significant perturbations in the biosynthesis of lipids, lipopolysaccharide, and peptidoglycan, central carbon metabolism, and oxidative stress. Importantly, lipid A modifications were surprisingly rapid in response to polymyxin treatment at clinically relevant concentrations. This is the first study to reveal the dynamics of polymyxin-induced cellular responses at the systems level, which highlights that combination therapy should be considered to minimize resistance to the last-line polymyxins. The results also provide much-needed mechanistic information which potentially benefits the discovery of new-generation polymyxins.Mei-Ling HanYan ZhuDarren J. CreekYu-Wei LinAlina D. GutuPaul HertzogTony PurcellHsin-Hui ShenSamuel M. MoskowitzTony VelkovJian LiAmerican Society for Microbiologyarticlelipid A modificationmetabolomicsPseudomonas aeruginosatranscriptomicsglycerophospholipidslipopolysaccharideMicrobiologyQR1-502ENmSystems, Vol 4, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	lipid A modification metabolomics Pseudomonas aeruginosa transcriptomics glycerophospholipids lipopolysaccharide Microbiology QR1-502
spellingShingle	lipid A modification metabolomics Pseudomonas aeruginosa transcriptomics glycerophospholipids lipopolysaccharide Microbiology QR1-502 Mei-Ling Han Yan Zhu Darren J. Creek Yu-Wei Lin Alina D. Gutu Paul Hertzog Tony Purcell Hsin-Hui Shen Samuel M. Moskowitz Tony Velkov Jian Li Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
description	ABSTRACT Polymyxins are a last-line therapy against multidrug-resistant Pseudomonas aeruginosa; however, resistance to polymyxins has been increasingly reported. Therefore, understanding the mechanisms of polymyxin activity and resistance is crucial for preserving their clinical usefulness. This study employed comparative metabolomics and transcriptomics to investigate the responses of polymyxin-susceptible P. aeruginosa PAK (polymyxin B MIC, 1 mg/liter) and its polymyxin-resistant pmrB mutant PAKpmrB6 (MIC, 16 mg/liter) to polymyxin B (4, 8, and 128 mg/liter) at 1, 4, and 24 h, respectively. Our results revealed that polymyxin B at 4 mg/liter induced different metabolic and transcriptomic responses between polymyxin-susceptible and -resistant P. aeruginosa. In strain PAK, polymyxin B significantly activated PmrAB and the mediated arn operon, leading to increased 4-amino-4-deoxy-L-arabinose (L-Ara4N) synthesis and the addition to lipid A. In contrast, polymyxin B did not increase lipid A modification in strain PAKpmrB6. Moreover, the syntheses of lipopolysaccharide and peptidoglycan were significantly decreased in strain PAK but increased in strain PAKpmrB6 due to polymyxin B treatment. In addition, 4 mg/liter polymyxin B significantly perturbed phospholipid and fatty acid levels and induced oxidative stress in strain PAK, but not in PAKpmrB6. Notably, the increased trehalose-6-phosphate levels indicate that polymyxin B potentially caused osmotic imbalance in both strains. Furthermore, 8 and 128 mg/liter polymyxin B significantly elevated lipoamino acid levels and decreased phospholipid levels but without dramatic changes in lipid A modification in wild-type and mutant strains, respectively. Overall, this systems study is the first to elucidate the complex and dynamic interactions of multiple cellular pathways associated with the polymyxin mode of action against P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa has been highlighted by the recent WHO Global Priority Pathogen List due to multidrug resistance. Without new antibiotics, polymyxins remain a last-line therapeutic option for this difficult-to-treat pathogen. The emergence of polymyxin resistance highlights the growing threat to our already very limited antibiotic armamentarium and the urgency to understand the exact mechanisms of polymyxin activity and resistance. Integration of the correlative metabolomics and transcriptomics results in the present study discovered that polymyxin treatment caused significant perturbations in the biosynthesis of lipids, lipopolysaccharide, and peptidoglycan, central carbon metabolism, and oxidative stress. Importantly, lipid A modifications were surprisingly rapid in response to polymyxin treatment at clinically relevant concentrations. This is the first study to reveal the dynamics of polymyxin-induced cellular responses at the systems level, which highlights that combination therapy should be considered to minimize resistance to the last-line polymyxins. The results also provide much-needed mechanistic information which potentially benefits the discovery of new-generation polymyxins.
format	article
author	Mei-Ling Han Yan Zhu Darren J. Creek Yu-Wei Lin Alina D. Gutu Paul Hertzog Tony Purcell Hsin-Hui Shen Samuel M. Moskowitz Tony Velkov Jian Li
author_facet	Mei-Ling Han Yan Zhu Darren J. Creek Yu-Wei Lin Alina D. Gutu Paul Hertzog Tony Purcell Hsin-Hui Shen Samuel M. Moskowitz Tony Velkov Jian Li
author_sort	Mei-Ling Han
title	Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_short	Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full	Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_fullStr	Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full_unstemmed	Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_sort	comparative metabolomics and transcriptomics reveal multiple pathways associated with polymyxin killing in <named-content content-type="genus-species">pseudomonas aeruginosa</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0216f278a9a149cba2b98925ca745bbd
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Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

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