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Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa

Spero, Melanie A. and Jones, Jeff and Lomenick, Brett and Chou, Tsui-Fen and Newman, Dianne K. (2022) Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa. Molecular Microbiology . ISSN 0950-382X. doi:10.1111/mmi.14972. (In Press)

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Pseudomonas aeruginosa is an opportunistic bacterial pathogen that often encounters hypoxic/anoxic environments within the host, which increases its tolerance to many conventional antibiotics. Towards 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.

Item Type:Article
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URLURL TypeDescription
Spero, Melanie A.0000-0003-3291-2138
Lomenick, Brett0000-0002-5023-9998
Chou, Tsui-Fen0000-0003-2410-2186
Newman, Dianne K.0000-0003-1647-1918
Additional Information:© 2022 John Wiley & Sons. Accepted manuscript online: 08 August 2022. Manuscript accepted: 04 August 2022. Manuscript revised: 31 July 2022. Manuscript received: 25 April 2022. Grants to D.K.N. from the NIH (1R21AI146987-02) and the Doren Family Foundation supported this research. M.A.S. was supported by a postdoctoral fellowship from the Cystic Fibrosis Foundation (SPERO19F0). We thank Megan Bergkessel (University of Dundee) for help with Tn-seq analyses, including providing custom scripts, and Nathan Dalleska and the Resnick Water and Environment Laboratory (Caltech) for help with metabolite analyses. We also thank John Bettinger for providing the python code used to analyze methionine oxidation levels via the ¹⁸O-H₂O₂ labeling method that he and colleagues developed (Bettinger et al.) The Proteome Exploration Laboratory was supported by NIH OD010788, NIH OD020013, the Betty and Gordon Moore Foundation through grant GBMF775 and the Beckman Institute at Caltech. Data Availability Statement: The proteomic data that supports the findings of this study are openly available in PRIDE at, accession number PXD033396.
Funding AgencyGrant Number
Doren Family FoundationUNSPECIFIED
Cystic Fibrosis FoundationSPERO19F0
Gordon and Betty Moore FoundationGBMF775
Caltech Beckman InstituteUNSPECIFIED
Record Number:CaltechAUTHORS:20220808-223822000
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Official Citation:Spero, M.A., Jones, J., Lomenick, B., Chou, T.-F. and Newman, D.K. (2022), Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa. Mol Microbiol. Accepted Author Manuscript.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:116160
Deposited By: George Porter
Deposited On:09 Aug 2022 23:19
Last Modified:09 Aug 2022 23:19

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