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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
Open accessAbstract
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-(1 H -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.
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“Structural analysis of C. albicans Erg11 demonstrated that while some substitutions involve residues that are exposed in the active-site cavity (directly affecting azole binding), others occur on the proximal surface of the enzyme and may indirectly contribute to azole resistance (for example, by influencing interactions with cytochrome P450 reductase)11.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [11]
In the citing paper
“the crystal structure of the Erg11 protein of C. albicans has been resolved”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [139]
In the citing paper
“other substitutions that are not predicted to directly interact with azole binding, such as the G450E substitution found on the fungal CYP51-specific β5-hairpin, may indirectly affect resistance through interaction with cytochrome P450 reductase–Erg11 interactions.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [139]
In the citing paper
“some substitutions, such as Y132F/H, K143R, G307S and S405F, are located on the exposed active-site cavity of the Erg11 protein and presumably directly influence or interfere with azole binding”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans (2020) · cites this paper as [139]
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Metadata
- Authors
- Hargrove, T. Y., Friggeri, L., Wawrzak, Z., Qi, A., Hoekstra, W. J., Schotzinger, R. J., York, J. D., Guengerich, F. P., & Lepesheva, G. I.
- Affiliations
- Vanderbilt University (US)
- Northwestern University (US)
- Viamet Pharmaceuticals (United States) (US)
- Corresponding author
- Lepesheva, Galina I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 292
- Issue
- 16
- Pages
- 6728-6743
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5399120
- OpenAlex
- W2593598577
- Cited by
- 444
- References
- 57
- Citations by year
- 2026: 67 · 2025: 82 · 2024: 49 · 2023: 64 · 2022: 55 · 2021: 30 · 2020: 39 · 2019: 25 · 2018: 24 · 2017: 9
- FWCI
- 21.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 GM067871)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Keywords
- Candida albicans, sterol 14α-demethylase, CYP51, cytochrome P450, azole antifungals, posaconazole, oteseconazole, fluconazole, ketoconazole, voriconazole, itraconazole, miconazole, clotrimazole, fungal sterol biosynthesis, drug resistance, Candida krusei, Candida glabrata, X-ray crystal structure, ligand binding, antifungal drug design
- MeSH terms
- Animals, Antifungal Agents, Azoles, Candida albicans, Crystallization, Fungal Proteins, Heme, Humans, Kinetics, Ligands, Microbial Sensitivity Tests, Protein Binding, Protein Conformation, Protons, Sterols, Rats, Sterol 14-Demethylase
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