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Chlorate Specifically Targets Oxidant-Starved, Antibiotic-Tolerant Populations of Pseudomonas aeruginosa Biofilms

Spero, Melanie A. and Newman, Dianne K. (2018) Chlorate Specifically Targets Oxidant-Starved, Antibiotic-Tolerant Populations of Pseudomonas aeruginosa Biofilms. mBio, 9 (5). Art. No. e01400-18. ISSN 2150-7511. PMCID PMC6156191. http://resolver.caltech.edu/CaltechAUTHORS:20181004-090829440

[img] PDF - Published Version
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[img] PDF (FIG S1 Drug sensitivity with CF lung nitrate concentrations.) - Supplemental Material
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[img] PDF (FIG S2 Nitrate and chlorate concentrations are stable in cell-free growth medium.) - Supplemental Material
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[img] PDF (FIG S3 nar genes are required for chlorate reduction and sensitivity in the ΔlasR mutant.) - Supplemental Material
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[img] PDF (FIG S4 Increased nitrate utilization in the ΔlasR mutant requires nar genes.) - Supplemental Material
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[img] Video (QuickTime) (MOVIE S1 Movie through a confocal z-stack of an aggregate biofilm population with increasing depth.) - Supplemental Material
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[img] Video (QuickTime) (MOVIE S2 Movie through a confocal z-stack of a tobramycin-treated aggregate biofilm population with increasing depth.) - Supplemental Material
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[img] Video (QuickTime) (MOVIE S3 Movie through a confocal z-stack of a chlorate-treated aggregate biofilm population with increasing depth.) - Supplemental Material
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[img] Video (QuickTime) (MOVIE S4 Movie through a confocal z-stack of a tobramycin- and chlorate-treated aggregate biofilm population with increasing depth.) - Supplemental Material
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Abstract

Nitrate respiration is a widespread mode of anaerobic energy generation used by many bacterial pathogens, and the respiratory nitrate reductase, Nar, has long been known to reduce chlorate to the toxic oxidizing agent chlorite. Here, we demonstrate the antibacterial activity of chlorate against Pseudomonas aeruginosa, a representative pathogen that can inhabit hypoxic or anoxic host microenvironments during infection. Aerobically grown P. aeruginosa cells are tobramycin sensitive but chlorate tolerant. In the absence of oxygen or an alternative electron acceptor, cells are tobramycin tolerant but chlorate sensitive via Nar-dependent reduction. The fact that chlorite, the product of chlorate reduction, is not detected in culture supernatants suggests that it may react rapidly and be retained intracellularly. Tobramycin and chlorate target distinct populations within metabolically stratified aggregate biofilms; tobramycin kills cells on the oxic periphery, whereas chlorate kills hypoxic and anoxic cells in the interior. In a matrix populated by multiple aggregates, tobramycin-mediated death of surface aggregates enables deeper oxygen penetration into the matrix, benefiting select aggregate populations by increasing survival and removing chlorate sensitivity. Finally, lasR mutants, which commonly arise in P. aeruginosa infections and are known to withstand conventional antibiotic treatment, are hypersensitive to chlorate. A lasR mutant shows a propensity to respire nitrate and reduce chlorate more rapidly than the wild type does, consistent with its heightened chlorate sensitivity. These findings illustrate chlorate’s potential to selectively target oxidant-starved pathogens, including physiological states and genotypes of P. aeruginosa that represent antibiotic-tolerant populations during infections.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1128/mbio.01400-18DOIArticle
https://mbio.asm.org/content/9/5/e01400-18/article-infoPublisherArticle
https://mbio.asm.org/content/9/5/e01400-18/figures-only#fig-data-supplementary-materialsPublisherSupplemental material
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156191/PubMed CentralArticle
ORCID:
AuthorORCID
Newman, Dianne K.0000-0003-1647-1918
Additional Information:© 2018 Spero and Newman. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Received June 26, 2018. Accepted August 22, 2018. Published online September 25, 2018. This work was supported by grants from the NIH (5R01HL117328-03 and 1R01AI127850-01A1) to D.K.N. We thank Nathan Dalleska and the Environmental Analysis Center (Caltech) for help with metabolite analyses, William DePas for help developing the ABBA protocol, and Elliot Snow for experimental assistance.
Funders:
Funding AgencyGrant Number
NIH5R01HL117328-03
NIH1R01AI127850-01A1
PubMed Central ID:PMC6156191
Record Number:CaltechAUTHORS:20181004-090829440
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181004-090829440
Official Citation:Spero MA, Newman DK. 2018. Chlorate specifically targets oxidant-starved, antibiotic-tolerant populations of Pseudomonas aeruginosa biofilms. mBio 9:e01400-18. https://doi.org/10.1128/mBio.01400-18.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90128
Collection:CaltechAUTHORS
Deposited By: Donna Wrublewski
Deposited On:04 Oct 2018 16:45
Last Modified:08 Oct 2018 15:33

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