Dataset Information

Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa

ABSTRACT: Pseudomonas aeruginosa is an opportunistic pathogen known to cause both acute and chronic infections. P. aeruginosa often encounters hypoxic/anoxic environments within the host, which increases its tolerance to many conventional antibiotics. Towards identifying novel therapeutic treatments, we have been exploring the potential of chlorate, a pro-drug that kills hypoxic/anoxic, antibiotic-tolerant P. aeruginosa populations. Chlorate kills P. aeruginosa when it is enzymatically reduced by hypoxically-induced nitrate reductase, thereby generating the toxic oxidizing agent, chlorite. To better assess its therapeutic potential, we investigated mechanisms of chlorate toxicity and resistance in P. aeruginosa. We combined transposon mutagenesis and high-throughput sequencing to identify genes that alter P. aeruginosa fitness during chlorate treatment. We found that methionine sulfoxide reductase (msr) genes, whose products repair oxidized methionine residues, support survival during chlorate stress. We showed that chlorate treatment leads to proteome-wide methionine oxidation, which is exacerbated in a ∆msrA∆msrB strain. Highly abundant proteins were the likeliest targets of methionine oxidation, including proteins that are abundant under standard conditions (e.g. ribosomes) and proteins that increase in abundance in response to chlorate stress (e.g. protein chaperones). The addition of exogenous methionine partially rescued P. aeruginosa survival during chlorate treatment, suggesting that widespread methionine oxidation contributes to cell death. Finally, we found that decreased nitrate reductase activity is a common mechanism of chlorate resistance. Because nitrate respiration likely sustains P. aeruginosa anaerobic growth and survival within the host, developing chlorate resistance would be expected to hinder pathogen fitness in such environments.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Pseudomonas Aeruginosa (strain Ucbpp-pa14)

TISSUE(S): Cell Culture

SUBMITTER: Jeff Jones

LAB HEAD: Tsui-Fen Chou

PROVIDER: PXD033396 | Pride | 2023-10-24

REPOSITORIES: Pride

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			Action	DRS
	Melanie_20210507_QE_Aur2hrs_WT-ClO3-1_250ng_004.raw	Raw
	Melanie_20210507_QE_Aur2hrs_WT-ClO3-2_250ng_005.raw	Raw
	Melanie_20210507_QE_Aur2hrs_WT-ClO3-3_250ng_006.raw	Raw
	Melanie_20210507_QE_Aur2hrs_WT-UN1_250ng_001.raw	Raw
	Melanie_20210507_QE_Aur2hrs_WT-UN2_250ng_002.raw	Raw

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Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa.

Spero Melanie A MA Jones Jeff J Lomenick Brett B Chou Tsui-Fen TF Newman Dianne K DK

Molecular microbiology 20220815 4

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that often encounters hypoxic/anoxic environments within the host, which increases its tolerance to many conventional antibiotics. Toward identifying novel treatments, we explored the therapeutic potential of chlorate, a pro-drug that kills hypoxic/anoxic, antibiotic-tolerant P. aeruginosa populations. While chlorate itself is relatively nontoxic, it is enzymatically reduced to the toxic oxidizing agent, chlorite, by hypoxically induc ...[more]

PMID: 36271736

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