Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa.

Autor: Spero MA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA., Jones J; Proteome Exploration Laboratory, Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA., Lomenick B; Proteome Exploration Laboratory, Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA., Chou TF; Proteome Exploration Laboratory, Beckman Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA., Newman DK; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.; Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, California, USA.
Jazyk: angličtina
Zdroj: Molecular microbiology [Mol Microbiol] 2022 Oct; Vol. 118 (4), pp. 321-335. Date of Electronic Publication: 2022 Aug 15.
DOI: 10.1111/mmi.14972
Abstrakt: 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 induced nitrate reductase. To better assess chlorate's therapeutic potential, we investigated mechanisms of chlorate toxicity and resistance in P. aeruginosa. We used transposon mutagenesis to identify genes that alter P. aeruginosa fitness during chlorate treatment, finding that methionine sulfoxide reductases (Msr), which repair oxidized methionine residues, support survival during chlorate stress. Chlorate treatment leads to proteome-wide methionine oxidation, which is exacerbated in a ∆msrA∆msrB strain. In response to chlorate, P. aeruginosa upregulates proteins involved in a wide range of functions, including metabolism, DNA replication/repair, protein repair, transcription, and translation, and these newly synthesized proteins are particularly vulnerable to methionine oxidation. The addition of exogenous methionine partially rescues P. aeruginosa survival during chlorate treatment, suggesting that widespread methionine oxidation contributes to death. Finally, we found that mutations that decrease nitrate reductase activity are a common mechanism of chlorate resistance.
(© 2022 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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