The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans
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Azole resistance in the pathogenic yeast Candida albicans is an emerging problem in the human immunodeficiency virus (HIV)-infected population. The target enzyme of the azole drugs is lanosterol 14alpha demethylase (Erg16p), a cytochrome P-450 enzyme in the biosynthetic pathway of ergosterol. Biochemical analysis demonstrates that Erg16p became less susceptible to fluconazole in isolate 13 in a series of isolates from an HIV-infected patient. PCR-single-strand conformation polymorphism (PCR-SSCP) analysis was used to scan for genomic alterations of ERG16 in the isolates that would cause this change in the enzyme in isolate 13. Alterations near the 3' end of the gene that were identified by PCR-SSCP were confirmed by DNA sequencing. A single amino acid substitution (R467K) that occurred in isolate 13 was identified in both alleles of ERG16. Allelic differences within the ERG16 gene, in the ERG16 promoter, and in the downstream THR1 gene were eliminated in isolate 13. The loss of allelic variation in this region of the genome is most likely the result of mitotic recombination or gene conversion. The R467K mutation and loss of allelic variation that occur in isolate 13 are likely responsible for the azole-resistant enzyme activity seen in this and subsequent isolates. The description of R467K represents the first point mutation to be identified within ERG16 of a clinical isolate of C. albicans that alters the fluconazole sensitivity of the enzyme.
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Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance, revealing a combination of various resistance mechanisms among the resistant strains.
“Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance (25–35), revealing a combination of various resistance mechanisms among the resistant strains (Table 1).”
From Potential role of lysine acetylation in the stepwise adaptation of <i>Candida albicans</i> to fluconazole (2025) · cites this paper as [29]
Cites
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
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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 · see citing works
Self-citationWhite, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
Self-citationPfaller, M. A., & Diekema, D. J. (2012) · Journal of Clinical Microbiology · doi:10.1128/jcm.00937-12 · Cited by 484 · see citing works
Perea, S., López-Ribot, J. L., Kirkpatrick, W. R., McAtee, R. K., Santillán, R. A., Martı́nez, M., Calabrese, D., Sanglard, D., & Patterson, T. F. (2001) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.45.10.2676-2684.2001 · Cited by 470 · see citing works
Resistance Mechanisms in Clinical Isolates of <i>Candida albicans</i>
White, T. C., Holleman, S., Dy, F., Mirels, L. F., & Stevens, D. A. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.6.1704-1713.2002 · Cited by 461 · see citing works
Self-citationMolecular Evolution of Antifungal Drug Resistance
Robbins, N., Caplan, T., & Cowen, L. E. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-030117-020345 · Cited by 441 · see citing works
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 · see citing works
Mechanisms of <i>Candida</i> Biofilm Drug Resistance
Taff, H. T., Mitchell, K. F., Edward, J. A., & Andes, D. R. (2013) · Future Microbiology · doi:10.2217/fmb.13.101 · Cited by 422 · see citing works
Coste, A., Turner, V., Ischer, F., Morschhäuser, J., Forche, A., Selmecki, A., Berman, J., Bille, J., & Sanglard, D. (2006) · Genetics · doi:10.1534/genetics.105.054767 · Cited by 385 · see citing works
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 · see citing works
Evolution of antifungal-drug resistance: mechanisms and pathogen fitness
Anderson, J. B. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1179 · Cited by 375 · see citing works
Arthington-Skaggs, B. A., Jradi, H., Desai, T., & Morrison, C. J. (1999) · Journal of Clinical Microbiology · doi:10.1128/jcm.37.10.3332-3337.1999 · Cited by 365 · see citing works
Morschhäuser, J., Barker, K. S., Liu, T. T., Blaß-Warmuth, J., Homayouni, R., & Rogers, P. D. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030164 · Cited by 355 · see citing works
Genetic and phenotypic intra-species variation in <i>Candida albicans</i>
Hirakawa, M. P., Martinez, D. A., Sakthikumar, S., Anderson, M. Z., Berlin, A., Gujja, S., Zeng, Q., Zisson, E., Wang, J. M., Greenberg, J. M., et al. (2015) · Genome Research · doi:10.1101/gr.174623.114 · Cited by 320 · see citing works
The evolution of drug resistance in clinical isolates of Candida albicans.
Ford, C. B., Funt, J. M., Abbey, D., Issi, L., Guiducci, C., Martinez, D. A., Delorey, T., Li, B. Y., White, T. C., Cuomo, C., et al. (2015) · eLife · doi:10.7554/elife.00662 · Cited by 348 · see citing works
Self-citationFranz, R., Kelly, S. L., Lamb, D. C., Kelly, D. E., Ruhnke, M., & Morschhäuser, J. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.12.3065 · Cited by 339 · see citing works
Forche, A., Alby, K., Schaefer, D., Johnson, A. D., Berman, J., & Bennett, R. J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060110 · Cited by 338 · see citing works
LaFayette, S. L., Collins, C., Zaas, A. K., Schell, W. A., Betancourt-Quiroz, M., Gunatilaka, A. A. L., Perfect, J. R., & Cowen, L. E. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001069 · Cited by 329 · see citing works
Selmecki, A., Gerami‐Nejad, M., Paulson, C., Forche, A., & Berman, J. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06176.x · Cited by 325 · see citing works
Pfaller, M. A., Andes, D., Diekema, D. J., Espinel-Ingroff, A., & Sheehan, D. (2010) · Drug Resistance Updates · doi:10.1016/j.drup.2010.09.002 · Cited by 314 · see citing works
Genotypic Evolution of Azole Resistance Mechanisms in Sequential <i>Candida albicans</i> Isolates
Coste, A., Selmecki, A., Forche, A., Diogo, D., Bougnoux, M.-E., d'Enfert, C., Berman, J., & Sanglard, D. (2007) · Eukaryotic Cell · doi:10.1128/ec.00151-07 · Cited by 305 · see citing works
An update on antifungal targets and mechanisms of resistance in<i>Candida</i><i>albicans</i>
Akins, R. A. (2005) · Medical Mycology · doi:10.1080/13693780500138971 · Cited by 291 · see citing works
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 · see citing works
Genomic Plasticity of the Human Fungal Pathogen Candida albicans
Selmecki, A., Forche, A., & Berman, J. (2010) · Eukaryotic Cell · doi:10.1128/ec.00060-10 · Cited by 247 · see citing works
Dunkel, N., Liu, T. T., Barker, K. S., Homayouni, R., Morschhäuser, J., & Rogers, P. D. (2008) · Eukaryotic Cell · doi:10.1128/ec.00103-08 · Cited by 236 · see citing works
Henry, K. W., Nickels, J. T., & Edlind, T. D. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.10.2693-2700.2000 · Cited by 216 · see citing works
Mechanism of Fluconazole Resistance in <i>Candida krusei</i>
Orozco, A. S., Higginbotham, L. M., Hitchcock, C. A., Parkinson, T., Falconer, D., Ibrahim, A. S., Ghannoum, M. A., & Filler, S. G. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.10.2645 · Cited by 218 · see citing works
Moran, G. P., Sanglard, D., Donnelly, S. M., Shanley, D. B., Sullivan, D. J., & Coleman, D. C. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.7.1819 · Cited by 197 · see citing works
Martel, C. M., Parker, J. E., Bader, O., Weig, M., Gross, U., Warrilow, A. G. S., Rolley, N., Kelly, D. E., & Kelly, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00348-10 · Cited by 168 · see citing works
Martel, C. M., Parker, J. E., Bader, O., Weig, M., Gross, U., Warrilow, A. G. S., Kelly, D. E., & Kelly, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00303-10 · Cited by 165 · see citing works
Marr, K. A., Lyons, C. N., Rustad, T., Bowden, R. A., & White, T. C. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.10.2584 · Cited by 166 · see citing works
Self-citationExpandable and reversible copy number amplification drives rapid adaptation to antifungal drugs
Todd, R. T., & Selmecki, A. (2020) · eLife · doi:10.7554/elife.58349 · Cited by 138 · see citing works
Experimental Induction of Fluconazole Resistance in <i>Candida tropicalis</i> ATCC 750
Barchiesi, F., Calabrese, D., Sanglard, D., Falconi Di Francesco, L., Caselli, F., Giannini, D., Giacometti, A., Gavaudan, S., & Scalise, G. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.6.1578-1584.2000 · Cited by 145 · see citing works
Arthington-Skaggs, B. A., Warnock, D. W., & Morrison, C. J. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.8.2081-2085.2000 · Cited by 142 · see citing works
Posteraro, B., Sanguinetti, M., Sanglard, D., La Sorda, M., Boccia, S., Romano, L., Morace, G., & Fadda, G. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03281.x · Cited by 143 · see citing works
Bennett, R. J., Forche, A., & Berman, J. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019604 · Cited by 118 · see citing works
Pfaller, M. A., Andes, D., Arendrup, M. C., Diekema, D. J., Espinel-Ingroff, A., Alexander, B. D., Brown, S. D., Chaturvedi, V., Fowler, C. L., Ghannoum, M. A., et al. (2011) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2011.03.002 · Cited by 130 · see citing works
Lysine Deacetylases Hda1 and Rpd3 Regulate Hsp90 Function thereby Governing Fungal Drug Resistance
Robbins, N., Leach, M. D., & Cowen, L. E. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.08.035 · Cited by 126 · see citing works
Jensen-Pergakes, K. L., Kennedy, M. A., Lees, N. D., Barbuch, R., Koegel, C., & Bard, M. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.5.1160 · Cited by 121 · see citing works
Morschhäuser, J. (2016) · Journal of Microbiology · doi:10.1007/s12275-016-5628-4 · Cited by 118 · see citing works
Azole Binding Properties of <i>Candida albicans</i> Sterol 14-α Demethylase (CaCYP51)
Warrilow, A. G. S., Martel, C. M., Parker, J. E., Melo, N., Lamb, D. C., Nes, W. D., Kelly, D. E., & Kelly, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00587-10 · Cited by 112 · see citing works
Formation of Azole-Resistant <i>Candida albicans</i> by Mutation of Sterol 14-Demethylase P450
Asai, K., Tsuchimori, N., Okonogi, K., Perfect, J. R., Gotoh, O., & Yoshida, Y. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.5.1163 · Cited by 102 · see citing works
Nishimoto, A. T., Sharma, C., & Rogers, P. D. (2020) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkz400 · Cited by 102 · see citing works
Sasse, C., Dunkel, N., Schäfer, T., Schneider, S., Dierolf, F., Ohlsen, K., & Morschhäuser, J. (2012) · Molecular Microbiology · doi:10.1111/j.1365-2958.2012.08210.x · Cited by 93 · see citing works
The alternative oxidase of Candida albicans causes reduced fluconazole susceptibility
Yan, L., Li, M., Cao, Y., Gao, P., Cao, Y., Wang, Y., & Jiang, Y. (2009) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkp273 · Cited by 89 · see citing works
In-vivo selection of an azole-resistant petite mutant of Candida glabrata
BOUCHARA, J.-P., LE BOUDOUIL, S., FILMON, R., ZOUHAIR, R., HALLET, J.-N., CHABASSE, D., RENIER, G., & DEFONTAINE, A. (2000) · Journal of Medical Microbiology · doi:10.1099/0022-1317-49-11-977 · Cited by 88 · see citing works
Miyazaki, Y., Geber, A., Miyazaki, H., Falconer, D., Parkinson, T., Hitchcock, C., Grimberg, B., Nyswaner, K., & Bennett, J. E. (1999) · Gene · doi:10.1016/s0378-1119(99)00263-2 · Cited by 71 · see citing works
Holmes, A. R., Tsao, S., Ong, S., Lamping, E., Niimi, K., Monk, B. C., Niimi, M., Kaneko, A., Holland, B. R., Schmid, J., et al. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05357.x · Cited by 68 · see citing works
Relationships between Respiration and Susceptibility to Azole Antifungals in <i>Candida glabrata</i>
Brun, S., Aubry, C., Lima, O., Filmon, R., Bergès, T., Chabasse, D., & Bouchara, J.-P. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.3.847-853.2003 · Cited by 64 · see citing works
The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in <i>Candida albicans</i>
Li, X., Cai, Q., Mei, H., Zhou, X., Shen, Y., Li, D., & Liu, W. (2015) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv070 · Cited by 64 · see citing works
Jia, N., Arthington-Skaggs, B., Lee, W., Pierson, C. A., Lees, N. D., Eckstein, J., Barbuch, R., & Bard, M. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.4.947-957.2002 · Cited by 61 · see citing works
Deciphering the Mrr1/Mdr1 Pathway in Azole Resistance of Candida auris
Li, J., Coste, A. T., Bachmann, D., Sanglard, D., & Lamoth, F. (2022) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00067-22 · Cited by 59 · see citing works
Wang, H., Kong, F., Sorrell, T. C., Wang, B., McNicholas, P., Pantarat, N., Ellis, D., Xiao, M., Widmer, F., & Chen, S. C. (2009) · BMC Microbiology · doi:10.1186/1471-2180-9-167 · Cited by 58 · see citing works
Within-Host Genomic Diversity of Candida albicans in Healthy Carriers
Sitterlé, E., Maufrais, C., Sertour, N., Palayret, M., d’Enfert, C., & Bougnoux, M.-E. (2019) · Scientific Reports · doi:10.1038/s41598-019-38768-4 · Cited by 51 · see citing works
Oliver, B. G., Song, J. L., Choiniere, J. H., & White, T. C. (2007) · Eukaryotic Cell · doi:10.1128/ec.00331-06 · Cited by 53 · see citing works
Self-citationMount, H. O., Revie, N. M., Todd, R. T., Anstett, K., Collins, C., Costanzo, M., Boone, C., Robbins, N., Selmecki, A., & Cowen, L. E. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007319 · Cited by 34 · see citing works
Evolutionary Dynamics of Candida albicans during <i>In Vitro</i> Evolution
Huang, M., McClellan, M., Berman, J., & Kao, K. C. (2011) · Eukaryotic Cell · doi:10.1128/ec.05168-11 · Cited by 34 · see citing works
Hoot, S. J., Brown, R. P., Oliver, B. G., & White, T. C. (2010) · Eukaryotic Cell · doi:10.1128/ec.00130-10 · Cited by 25 · see citing works
Self-citationAaron, K. E., Pierson, C. A., Lees, N. D., & Bard, M. (2001) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2001.tb00020.x · Cited by 22 · see citing works
Dunkel, N., & Morschhäuser, J. (2011) · Eukaryotic Cell · doi:10.1128/ec.00281-10 · Cited by 20 · see citing works
Pierson, C. A., Jia, N., Mo, C., Lees, N. D., Sturm, A. M., Eckstein, J., Barbuch, R., & Bard, M. (2004) · Medical Mycology · doi:10.1080/1369378032000141471 · Cited by 19 · see citing works
A Proteomic Landscape of Candida albicans in the Stepwise Evolution to Fluconazole Resistance
Song, N., Zhou, X., Li, D., Li, X., & Liu, W. (2022) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02105-21 · Cited by 17 · see citing works
Lee, Y., Liston, S. D., Lee, D., Robbins, N., & Cowen, L. E. (2022) · iScience · doi:10.1016/j.isci.2022.104432 · Cited by 18 · see citing works
Song, N., Huang, Y., Zhou, X., Li, D., Liu, W., & Li, X. (2025) · Microbiology Spectrum · doi:10.1128/spectrum.02797-24
- Authors
- White, T. C.
- Affiliations
- Center for Infectious Disease Research (US)
- Corresponding author
- White, T C
- ORCID
- White, T C
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1997-07
- Volume
- 41
- Issue
- 7
- Pages
- 1488-1494
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC163945
- OpenAlex
- W2105638437
- Cited by
- 292
- References
- 1
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 1 · 2022: 7 · 2021: 3 · 2020: 7 · 2019: 13 · 2018: 4 · 2017: 10 · 2016: 5 · 2015: 7 · 2014: 15 · 2013: 9 · 2012: 9
- FWCI
- 17.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of Texas Health Science Center at San Antonio
- National Institute of Dental and Craniofacial Research (R01DE011367, R01 DE-11367)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida albicans, azole resistance, fluconazole resistance, lanosterol 14α-demethylase, point mutations, mitotic recombination, gene conversion, HIV infection, cytochrome P450, ergosterol biosynthesis
- MeSH terms
- Alleles, Antifungal Agents, Base Sequence, Candida albicans, Cloning, Molecular, Cytochrome P-450 Enzyme System, Drug Resistance, Microbial, Humans, Molecular Sequence Data, Mutation, Oxidoreductases, Promoter Regions, Genetic, Genetic Variation, Fluconazole, Polymerase Chain Reaction, Sequence Analysis, Polymorphism, Single-Stranded Conformational, Sterol 14-Demethylase
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