A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance
| Autor: | Alex K. Lancaster, Ruth Scherz-Shouval, Bruce Tidor, Benjamin Vincent, Stephen L. Buchwald, Susan Lindquist, Jean-Baptiste Langlois, Raja Srinivas, Luke Whitesell |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology chemistry.chemical_classification biology 030106 microbiology Clinical Biochemistry Virulence Drug resistance biology.organism_classification Biochemistry Microbiology Fungicide 03 medical and health sciences 030104 developmental biology Immune system chemistry Drug Discovery Molecular Medicine Macrophage Azole Candida albicans Molecular Biology Phagosome |
| Zdroj: | Cell Chemical Biology. 23:978-991 |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2016.06.016 |
| Popis: | Summary 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 bc 1 . 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 bc 1 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. |
| Databáze: | OpenAIRE |
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