Inhibiting fungal multidrug resistance by disrupting an activator–Mediator interaction

Joy L. Nishikawa, Andras Boeszoermenyi, Luis A. Vale-Silva, Riccardo Torelli, Brunella Posteraro, Yoo-Jin Sohn, Fei Ji, Vladimir Gelev, Dominique Sanglard, Maurizio Sanguinetti, Ruslan I. Sadreyev, Goutam Mukherjee, Jayaram Bhyravabhotla, Sara J. Buhrlage, Nathanael S. Gray, Gerhard Wagner (), Anders M. Näär () and Haribabu Arthanari ()
Additional contact information
Joy L. Nishikawa: Massachusetts General Hospital Cancer Center
Andras Boeszoermenyi: Harvard Medical School
Luis A. Vale-Silva: Institute of Microbiology, University Hospital Lausanne and University Hospital Center
Riccardo Torelli: Institute of Microbiology, Università Cattolica del Sacro Cuore
Brunella Posteraro: Institute of Public Health, Università Cattolica del Sacro Cuore
Yoo-Jin Sohn: Massachusetts General Hospital Cancer Center
Fei Ji: Massachusetts General Hospital, Boston
Vladimir Gelev: Faculty of Chemistry and Pharmacy, Sofia University
Dominique Sanglard: Institute of Microbiology, University Hospital Lausanne and University Hospital Center
Maurizio Sanguinetti: Institute of Microbiology, Università Cattolica del Sacro Cuore
Ruslan I. Sadreyev: Massachusetts General Hospital, Boston
Goutam Mukherjee: Indian Institute of Technology Delhi
Jayaram Bhyravabhotla: Indian Institute of Technology Delhi
Sara J. Buhrlage: Harvard Medical School
Nathanael S. Gray: Harvard Medical School
Gerhard Wagner: Harvard Medical School
Anders M. Näär: Massachusetts General Hospital Cancer Center
Haribabu Arthanari: Harvard Medical School

Nature, 2016, vol. 530, issue 7591, 485-489

Abstract: A small molecule, inhibitor of a protein–protein interaction between the transcription factor Pdr1 and the Med15 subunit of Mediator in the fungal pathogen Candida glabrata, is identified and characterized here; the compound iKIX1 inhibits Pdr1-mediated gene activation and resensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models of disseminated and urinary tract infection.

Date: 2016
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DOI: 10.1038/nature16963

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