Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control
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Author(s)
Belenky, Peter
Park, Jihye
Kim, Sun H.
Moskowitz, Samuel M.
Meylan, Sylvain
Porter, Caroline
Yang, Jason Hung-Ying
Gutierrez, Arnaud
Lobritz, Michael Andrew
Collins, James J.
Date Issued
January 2017
Journal
Cell Chemical Biology
Publisher
Elsevier BV
Citation
Meylan, Sylvain et al. “Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas Aeruginosa via Tricarboxylic Acid Cycle Control.” Cell Chemical Biology 24, 2 (February 2017): 195–206 © 2017 Elsevier Ltd
Version
Author's final manuscript
Abstract
Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle. In contrast, we find that glyoxylate induces phenotypic tolerance by inhibiting cellular respiration with acetyl-coenzyme A diversion through the glyoxylate shunt, despite drug import. Collectively, this work demonstrates that TCA cycle activity is important for both aminoglycoside uptake and downstream lethality and identifies a potential strategy for potentiating aminoglycoside treatment of P. aeruginosa infections. Keyword: aminoglycoside susceptibility; Pseudomonas aeruginosa; TCA cycle; respiration; electron transport chain; fumarate; glyoxylate; biochemical persistence; LC-MS metabolomics
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CHEMBIOL.2016.12.015
