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Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates |
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| Authors: | Youngsaye Willmen Vincent Benjamin Hartland Cathy L Morgan Barbara J Buhrlage Sara J Johnston Stephen Bittker Joshua A MacPherson Lawrence Dandapani Sivaraman Palmer Michelle Whitesell Luke Lindquist Susan Schreiber Stuart L Munoz Benito |
| Affiliation: | Chemical Biology Platform and Probe Development Center, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. |
| Abstract: | The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria. |
| Keywords: | Candidaalbicans Fluconazole Antifungal Chemosensitizer Molecular Libraries Probe Production Centers Network (MLPCN) |
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