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

The Journal of biological chemistry, 2017-04, Vol.292 (16), p.6728-6743 [Peer Reviewed Journal]

2017 © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2017 by The American Society for Biochemistry and Molecular Biology, Inc. ;2017 by The American Society for Biochemistry and Molecular Biology, Inc. 2017 The American Society for Biochemistry and Molecular Biology, Inc. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M117.778308 ;PMID: 28258218

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Title:
Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis
Author: Hargrove, Tatiana Y. ; Friggeri, Laura ; Wawrzak, Zdzislaw ; Qi, Aidong ; Hoekstra, William J. ; Schotzinger, Robert J. ; York, John D. ; Guengerich, F. Peter ; Lepesheva, Galina I.
Subjects: Animals ; Antifungal Agents - chemistry ; antifungal drugs ; Azoles - chemistry ; Candida albicans ; Candida albicans - enzymology ; Crystallization ; cytochrome P450 ; enzyme inhibitor ; enzyme kinetics ; Enzymology ; Fungal Proteins - chemistry ; Heme - chemistry ; Humans ; Kinetics ; Ligands ; Microbial Sensitivity Tests ; Protein Binding ; Protein Conformation ; Protons ; Rats ; sterol 14 alpha-demethylase (CYP51) ; Sterol 14-Demethylase - chemistry ; sterol biosynthesis ; Sterols - biosynthesis ; X-ray crystallography
Is Part Of: The Journal of biological chemistry, 2017-04, Vol.292 (16), p.6728-6743
Description: 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 tetrazole-based 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 broad-spectrum antifungals.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M117.778308
PMID: 28258218
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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

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