A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance
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A fungal-selective.pdf
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Author(s)
Srinivas, Raja
Lancaster, Alex K.
Scherz-Shouval, Ruth
Whitesell, Luke
Vincent, Benjamin Matteson
Langlois, Jean-Baptiste
Tidor, Bruce
Buchwald, Stephen Leffler
Lindquist, Susan
Date Issued
August 2016
Journal
Cell Chemical Biology
Publisher
Elsevier
Citation
Vincent, Benjamin M. et al. “A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance.” Cell Chemical Biology 23, 8 (August 2016): 978–991 © 2016 Elsevier Ltd
Version
Author's final manuscript
Abstract
To cause disease, a microbial pathogen must adapt to the challenges of its host environment. The leading fungal pathogen Candida albicans colonizes nutrient-poor bodily niches, withstands attack from the immune system, and tolerates treatment with azole antifungals, often evolving resistance. To discover agents that block these adaptive strategies, we screened 300,000 compounds for inhibition of azole tolerance in a drug-resistant Candida isolate. We identified a novel indazole derivative that converts azoles from fungistatic to fungicidal drugs by selective inhibition of mitochondrial cytochrome bc1. We synthesized 103 analogs to optimize potency (half maximal inhibitory concentration 0.4 μM) and fungal selectivity (28-fold over human). In addition to reducing azole resistance, targeting cytochrome bc₁ prevents C. albicans from adapting to the nutrient-deprived macrophage phagosome and greatly curtails its virulence in mice. Inhibiting mitochondrial respiration and restricting metabolic flexibility with this synthetically tractable chemotype provides an attractive therapeutic strategy to limit both fungal virulence and drug resistance.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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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.2016.06.016
