A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance
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 dis...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/111146 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0003-3875-4775 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1811082605962985472 |
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| author | Srinivas, Raja Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Vincent, Benjamin Matteson Langlois, Jean-Baptiste Tidor, Bruce Buchwald, Stephen Leffler Lindquist, Susan |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Srinivas, Raja Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Vincent, Benjamin Matteson Langlois, Jean-Baptiste Tidor, Bruce Buchwald, Stephen Leffler Lindquist, Susan |
| author_sort | Srinivas, Raja |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:06:04Z |
| format | Article |
| id | mit-1721.1/111146 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:06:04Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1111462022-09-28T00:10:06Z A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance Srinivas, Raja Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Vincent, Benjamin Matteson Langlois, Jean-Baptiste Tidor, Bruce Buchwald, Stephen Leffler Lindquist, Susan 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 Vincent, Benjamin Matteson Langlois, Jean-Baptiste Tidor, Bruce Buchwald, Stephen Leffler Lindquist, Susan 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. National Institutes of Health (U.S.) (GM46059) 2017-09-07T15:48:36Z 2017-09-07T15:48:36Z 2016-08 2016-05 Article http://purl.org/eprint/type/JournalArticle 2451-9456 http://hdl.handle.net/1721.1/111146 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 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0003-3875-4775 https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1016/j.chembiol.2016.06.016 Cell Chemical Biology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Srinivas, Raja Lancaster, Alex K. Scherz-Shouval, Ruth Whitesell, Luke Vincent, Benjamin Matteson Langlois, Jean-Baptiste Tidor, Bruce Buchwald, Stephen Leffler Lindquist, Susan A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title | A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title_full | A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title_fullStr | A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title_full_unstemmed | A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title_short | A Fungal-Selective Cytochrome bc₁ Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance |
| title_sort | fungal selective cytochrome bc₁ inhibitor impairs virulence and prevents the evolution of drug resistance |
| url | http://hdl.handle.net/1721.1/111146 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0003-3875-4775 https://orcid.org/0000-0003-1307-882X |
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