Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis

Tatiana Y. Hargrove, Laura Friggeri, Zdzislaw Wawrzak, Aidong Qi, William J. Hoekstra, Robert J. Schotzinger, John D. York, F. Peter Guengerich, Galina I. Lepesheva*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    97 Scopus citations

    Abstract

    With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazolebased drug candidate, VT-1161 (oteseconazole: (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-Tetrazol-1-yl)-1-(5-(4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against Candida krusei and Candida glabrata, pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broadspectrum antifungals.

    Original languageEnglish (US)
    Pages (from-to)6728-6743
    Number of pages16
    JournalJournal of Biological Chemistry
    Volume292
    Issue number16
    DOIs
    StatePublished - Apr 21 2017

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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