The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 46,047
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
Hidden Killers: Human Fungal Infections
Brown, G. D., Denning, D. W., Gow, N. A. R., Levitz, S. M., Netea, M. G., & White, T. C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004404 · Cited by 4,284
Pappas, P. G., Kauffman, C. A., Andes, D. R., Clancy, C. J., Marr, K. A., Ostrosky-Zeichner, L., Reboli, A. C., Schuster, M. G., Vazquez, J. A., Walsh, T. J., et al. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/civ933 · Cited by 4,200
Krissinel, E., & Henrick, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904026460 · Cited by 3,788
Pappas, P. G., Kauffman, C. A., Andes, D., Benjamin, D. K., Calandra, T. F., Edwards, J. E., Filler, S. G., Fisher, J. F., Kullberg, B.-J., Zeichner, L. O., et al. (2009) · Clinical Infectious Diseases · doi:10.1086/596757 · Cited by 3,191
Cytochrome P-450: Structure, Mechanism, and Biochemistry
de Montellano, O., & Paul, R. (1986) · Medical Entomology and Zoology · Cited by 2,663
Cytochrome P450: Structure, mechanism, and biochemistry
PRYOR, W. A. (1996) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(96)83807-x · Cited by 1,603
Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance
White, T. C., Marr, K. A., & Bowden, R. A. (1998) · Clinical Microbiology Reviews · doi:10.1128/cmr.11.2.382 · Cited by 1,353
The Catalytic Pathway of Cytochrome P450cam at Atomic Resolution
Schlichting, I., Berendzen, J., Chu, K., Stock, A., Maves, S. A., Benson, D. E., Sweet, R. M., Ringe, D., Petsko, G. A., & Sligar, S. G. (2000) · Science · doi:10.1126/science.287.5458.1615 · Cited by 1,349
Kullberg, B. J., & Arendrup, M. C. (2015) · New England Journal of Medicine · doi:10.1056/nejmra1315399 · Cited by 1,315
A graphical user interface to the CCP 4 program suite
Potterton, E. A., Briggs, P., Turkenburg, M., & Dodson, E. J. (2003) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444903008126 · Cited by 1,216
Gotoh, O. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)48462-1 · Cited by 1,204
Molecular Evidence for the Early Colonization of Land by Fungi and Plants
Heckman, D. S., Geiser, D. M., Eidell, B. R., Stauffer, R. L., Kardos, N. L., & Hedges, S. B. (2001) · Science · doi:10.1126/science.1061457 · Cited by 1,020
The Early Evolution of Eukaryotes: A Geological Perspective
Knoll, A. H. (1992) · Science · doi:10.1126/science.1585174 · Cited by 684
Epidemiology and risk factors for invasive candidiasis
Yapar, N. (2014) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s40160 · Cited by 610
Candida albicans cell-type switching and functional plasticity in the mammalian host
Noble, S. M., Gianetti, B. A., & Witchley, J. N. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.157 · Cited by 548
Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms
Lepesheva, G. I., & Waterman, M. R. (2006) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2006.07.018 · Cited by 494
Self-citationHow to bolster the antifungal pipeline
Denning, D. W., & Bromley, M. (2015) · Science · doi:10.1126/science.aaa6097 · Cited by 489
Azole antifungal agents: Emphasis on new triazoles
Saag, M. S., & Dismukes, W. E. (1988) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.32.1.1 · Cited by 474
Molecular basis of resistance to azole antifungals.
Lupetti, A. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02280-3 · Cited by 449
Marichal, P., Koymans, L., Willemsens, S., Bellens, D., Verhasselt, P., Luyten, W., Borgers, M., Ramaekers, F. C. S., Odds, F. C., & Vanden Bossche, H. (1999) · Microbiology · doi:10.1099/00221287-145-10-2701 · Cited by 382
Ene, I. V., Adya, A. K., Wehmeier, S., Brand, A. C., MacCallum, D. M., Gow, N. A. R., & Brown, A. J. P. (2012) · Cellular Microbiology · doi:10.1111/j.1462-5822.2012.01813.x · Cited by 313
Morio, F., Loge, C., Besse, B., Hennequin, C., & Le Pape, P. (2010) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2009.11.006 · Cited by 279
Triazole Antifungal Agents in Invasive Fungal Infections
Lass‐Flörl, C. (2011) · Drugs · doi:10.2165/11596540-000000000-00000 · Cited by 276
Candidemia and invasive candidiasis in adults: A narrative review
Antinori, S., Milazzo, L., Sollima, S., Galli, M., & Corbellino, M. (2016) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2016.06.029 · Cited by 259
Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives
Zhang, W., Ramamoorthy, Y., Kilicarslan, T., Nolte, H., Tyndale, R. F., & Sellers, E. M. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.3.314 · Cited by 252
Design and optimization of highly-selective fungal CYP51 inhibitors
Hoekstra, W. J., Garvey, E. P., Moore, W. R., Rafferty, S. W., Yates, C. M., & Schotzinger, R. J. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.05.068 · Cited by 195
Self-citationCell biology of Candida albicans–host interactions
Dantas, A. D. S., Lee, K. K., Raziunaite, I., Schaefer, K., Wagener, J., Yadav, B., & Gow, N. A. R. (2016) · Current Opinion in Microbiology · doi:10.1016/j.mib.2016.08.006 · Cited by 179
Hargrove, T. Y., Wawrzak, Z., Lamb, D. C., Guengerich, F. P., & Lepesheva, G. I. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677310 · Cited by 168
Self-citationStructural basis for conservation in the CYP51 family
Lepesheva, G. I., & Waterman, M. R. (2010) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2010.06.006 · Cited by 147
Self-citationLepesheva, G. I., Hargrove, T. Y., Anderson, S. M., Kleshchenko, Y. Y., Furtak, V. A., Wawrzak, Z., Villalta, F., & Waterman, M. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.133215 · Cited by 146
Self-citationLepesheva, G. I., Ott, R. D., Hargrove, T. Y., Kleshchenko, Y. Y., Schuster, I., Nes, W. D., Hill, G. C., Villalta, F., & Waterman, M. R. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2007.10.011 · Cited by 138
Self-citationHargrove, T. Y., Wawrzak, Z., Liu, J., Nes, W. D., Waterman, M. R., & Lepesheva, G. I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.237099 · Cited by 125
Self-citationLepesheva, G. I., Zaitseva, N. G., Nes, W. D., Zhou, W., Arase, M., Liu, J., Hill, G. C., & Waterman, M. R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m510317200 · Cited by 120
Self-citationMorschhäuser, J. (2016) · Journal of Microbiology · doi:10.1007/s12275-016-5628-4 · Cited by 118
Lepesheva, G. I., Park, H.-W., Hargrove, T. Y., Vanhollebeke, B., Wawrzak, Z., Harp, J. M., Sundaramoorthy, M., Nes, W. D., Pays, É., Chaudhuri, M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.067470 · Cited by 116
Self-citationCandida albicans Biofilm Development and Its Genetic Control
Desai, J. V., & Mitchell, A. P. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mb-0005-2014 · Cited by 94
Garvey, E. P., HOEKSTRA, W., Schotzinger, R. J., Sobel, J. D., Lilly, E. A., & Fidel, P. L. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00185-15 · Cited by 84
Self-citationCYP51 from Trypanosoma brucei Is Obtusifoliol-Specific
Lepesheva, G. I., Nes, W. D., Zhou, W., Hill, G. C., & Waterman, M. R. (2004) · Biochemistry · doi:10.1021/bi048967t · Cited by 79
Self-citationHargrove, T. Y., Wawrzak, Z., Alexander, P. W., Chaplin, J. H., Keenan, M., Charman, S. A., Perez, C. J., Waterman, M. R., Chatelain, E., & Lepesheva, G. I. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.497990 · Cited by 79
Self-citationSchell, W. A., Jones, A. M., Garvey, E. P., Hoekstra, W. J., Schotzinger, R. J., & Alexander, B. D. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01817-16 · Cited by 74
Self-citationRole of isavuconazole in the treatment of invasive fungal infections
Wilson, D. T., DiMondi, V. P., Johnson, S., Jones, T. M., & Drew, R. H. (2016) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s90335 · Cited by 72
Hargrove, T. Y., Wawrzak, Z., Liu, J., Waterman, M. R., Nes, W. D., & Lepesheva, G. I. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m021865 · Cited by 67
Self-citationAndriani, G., Amata, E., Beatty, J. W., Clements, Z. T., Coffey, B. J., Courtemanche, G., Devine, W. G., Erath, J., Juda, C. E., Wawrzak, Z., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400012e · Cited by 66
Self-citationLepesheva, G. I., Hargrove, T. Y., Rachakonda, G., Wawrzak, Z., Pomel, S., Cojean, S., Nde, P. N., Nes, W. D., Locuson, C. W., Calcutt, M. W., et al. (2015) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiv228 · Cited by 66
Self-citationHargrove, T. Y., Friggeri, L., Wawrzak, Z., Sivakumaran, S., Yazlovitskaya, E. M., Hiebert, S. W., Guengerich, F. P., Waterman, M. R., & Lepesheva, G. I. (2016) · Journal of Lipid Research · doi:10.1194/jlr.m069229 · Cited by 61
Self-citationSterol biosynthesis inhibitors
(1989) · Biomedicine & Pharmacotherapy · doi:10.1016/0753-3322(89)90024-3 · Cited by 61
Friggeri, L., Hargrove, T. Y., Rachakonda, G., Williams, A. D., Wawrzak, Z., Santo, R. D., Vita, D. D., Waterman, M. R., Tortorella, S., Villalta, F., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500739f · Cited by 45
Self-citationLepesheva, G. I., Podust, L. M., Bellamine, A., & Waterman, M. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102767200 · Cited by 45
Self-citationMane, A. K., Vidhate, P., Kusro, C., Waman, V., Saxena, V., Kulkarni‐Kale, U., & Risbud, A. (2015) · Mycoses · doi:10.1111/myc.12439 · Cited by 41
Hoekstra, W. J., Hargrove, T. Y., Wawrzak, Z., Batista, D. D. G. J., da Silva, C. F., Nefertiti, A. S. G., Rachakonda, G., Schotzinger, R. J., Villalta, F., Soeiro, M. D. N. C., et al. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02287-15 · Cited by 37
Self-citationEffect of imidazole antifungals on the development of germ tubes by strains of Candida albicans
Johnson, E. M., Richardson, M. D., & Warnock, D. W. (1983) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/12.4.303 · Cited by 32
Lepesheva, G. I., Strushkevich, N. V., & Usanov, S. A. (1999) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/s0167-4838(99)00156-9 · Cited by 30
Self-citationHow can We Bolster the Antifungal Drug Discovery Pipeline?
Jampílek, J. (2016) · Future Medicinal Chemistry · doi:10.4155/fmc-2016-0124 · Cited by 30
Cherkesova, T. S., Hargrove, T. Y., Vanrell, M. C., Ges, I. A., Usanov, S. A., Romano, P. S., & Lepesheva, G. I. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.08.030 · Cited by 21
Self-citationJeong, W., Haywood, P., Shanmuganathan, N., Lindsay, J., Urbancic, K. F., Ananda-Rajah, M. R., Chen, W., Bajel, A. R., Ritchie, D., Grigg, A., et al. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkw322 · Cited by 20
Cited by
Sorted by citations
Molecular mechanisms governing antifungal drug resistance
Lee, Y., Robbins, N., & Cowen, L. E. (2023) · npj Antimicrobials and Resistance · doi:10.1038/s44259-023-00007-2 · Cited by 304
Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions
Guengerich, F. P., & Yoshimoto, F. K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00031 · Cited by 298
Self-citationShafiei, M., Peyton, L., Hashemzadeh, M., & Foroumadi, A. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104240 · Cited by 295
The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors
Zhang, J., Li, L., Lv, Q., Yan, L., Wang, Y., & Jiang, Y. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00691 · Cited by 261
Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species
Sobel, J. D., & Sobel, R. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1476490 · Cited by 168
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
