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  3. A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance

A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance

  • Cell Chem Biol. 2016 Aug 18;23(8):978-991. doi: 10.1016/j.chembiol.2016.06.016.
Benjamin M Vincent 1,  Jean-Baptiste Langlois 2,  Raja Srinivas 3,  Alex K Lancaster 4,  Ruth Scherz-Shouval 4,  Luke Whitesell 4,  Bruce Tidor 3,  Stephen L Buchwald 2,  Susan Lindquist 5
Affiliations

Affiliations

  • 1 Microbiology Graduate Program, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 4 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • 5 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: lindquist_admin@wi.mit.edu.
PMID: 27524297 DOI: 10.1016/j.chembiol.2016.06.016
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 ?M) 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.

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