Cited by 461Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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Resistance Mechanisms in Clinical Isolates of Candida albicans

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White, Theodore C., Holleman, Scott, Dy, Francis, Mirels, Laurence F., Stevens, David A.·2002·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.46.6.1704-1713.2002PMC PMC127245

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Abstract

Resistance to azole antifungals continues to be a significant problem in the common fungal pathogen Candida albicans . Many of the molecular mechanisms of resistance have been defined with matched sets of susceptible and resistant clinical isolates from the same strain. Mechanisms that have been identified include alterations in the gene encoding the target enzyme ERG11 or overexpression of efflux pump genes including CDR1 , CDR2 , and MDR1 . In the present study, a collection of unmatched clinical isolates of C. albicans was analyzed for the known molecular mechanisms of resistance by standard methods. The collection was assembled so that approximately half of the isolates were resistant to azole drugs. Extensive cross-resistance was observed for fluconazole, clotrimazole, itraconazole, and ketoconazole. Northern blotting analyses indicated that overexpression of CDR1 and CDR2 correlates with resistance, suggesting that the two genes may be coregulated. MDR1 overexpression was observed infrequently in some resistant isolates. Overexpression of FLU1 , an efflux pump gene related to MDR1 , did not correlate with resistance, nor did overexpression of ERG11 . Limited analysis of the ERG11 gene sequence identified several point mutations in resistant isolates; these mutations have been described previously. Two of the most common point mutations in ERG11 associated with resistance, D116E and E266D, were tested by restriction fragment length polymorphism analysis of the isolates from this collection. The results indicated that the two mutations occur frequently in different isolates of C. albicans and are not reliably associated with resistance. These analyses emphasize the diversity of mechanisms that result in a phenotype of azole resistance. They suggest that the resistance mechanisms identified in matched sets of susceptible and resistant isolates are not sufficient to explain resistance in a collection of unmatched clinical isolates and that additional mechanisms have yet to be discovered.

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Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589
National Committee for Clinical Laboratory Standards
Bruck, E. (1980) · PEDIATRICS · doi:10.1542/peds.65.1.187 · Cited by 14,736
A ten-minute DNA preparation from yeast efficiently releases autonomous plasmids for transformaion of Escherichia coli
Hoffman, C. S., & Winston, F. (1987) · Gene · doi:10.1016/0378-1119(87)90131-4 · Cited by 2,492
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
Self-citation
Development of Interpretive Breakpoints for Antifungal Susceptibility Testing: Conceptual Framework and Analysis of In Vitro-In Vivo Correlation Data for Fluconazole, Itraconazole, and Candida Infections
Rex, J. H., Pfaller, M. A., Galgiani, J. N., Bartlett, M. S., Espinel-Ingroff, A., Ghannoum, M. A., Lancaster, M., Odds, F. C., Rinaldi, M. G., Walsh, T. J., et al. (1997) · Clinical Infectious Diseases · doi:10.1093/clinids/24.2.235 · Cited by 855
Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters
Sanglard, D., Kuchler, K., Ischer, F., Pagani, J. L., Monod, M., & Bille, J. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.11.2378 · Cited by 815
Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612
Self-citation
Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene
Sanglard, D., Ischer, F., Monod, M., & Bille, J. (1997) · Microbiology · doi:10.1099/00221287-143-2-405 · Cited by 587
Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals
Prasad, R., De Wergifosse, P., Goffeau, A., & Balzi, E. (1995) · Current Genetics · doi:10.1007/bf00352101 · Cited by 486
Prevalence of Molecular Mechanisms of Resistance to Azole Antifungal Agents in Candida albicans Strains Displaying High-Level Fluconazole Resistance Isolated from Human Immunodeficiency Virus-Infected Patients
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
Amino Acid Substitutions in the Cytochrome P-450 Lanosterol 14α-Demethylase (CYP51A1) from Azole-Resistant Candida albicans Clinical Isolates Contribute to Resistance to Azole Antifungal Agents
Sanglard, D., Ischer, F., Koymans, L. M. H., & Billé, J. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.2.241 · Cited by 465
Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans
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
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White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1488 · Cited by 292
Self-citation
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Redding, S., Smith, J., Farinacci, G., Rinaldi, M., Fothergill, A., Rhine-Chalberg, J., & Pfaller, M. (1994) · Clinical Infectious Diseases · doi:10.1093/clinids/18.2.240 · Cited by 269
Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia
Nolte, F. S., Parkinson, T., Falconer, D. J., Dix, S. P., Williams, J. M., Gilmore, C., Geller, R., & Wingard, J. R. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.1.196 · Cited by 220
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Lopez-Ribot, J. L., McAtee, R. K., Lee, L. N., Kirkpatrick, W. R., White, T. C., Sanglard, D., & Patterson, T. F. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.11.2932 · Cited by 210
Self-citation
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Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate
Fling, M. E., Kopf, J., Tamarkin, A., Gorman, J. A., Smith, H. A., & Koltin, Y. (1991) · Molecular and General Genetics MGG · doi:10.1007/bf00259685 · Cited by 205
Molecular and Phenotypic Characterization of Genotypic Candida albicans Subgroups and Comparison with Candida dubliniensis and Candida stellatoidea
McCullough, M. J., Clemons, K. V., & Stevens, D. A. (1999) · Journal of Clinical Microbiology · doi:10.1128/jcm.37.2.417-421.1999 · Cited by 202
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Pfaller, M. A., Rhine-Chalberg, J., Redding, S. W., Smith, J. D., Farinacci, G. C., Fothergill, A. W., & Rinaldi, M. G. (1994) · Journal of Clinical Microbiology · doi:10.1128/jcm.32.1.59-64.1994 · Cited by 197
The yeast Candida albicans has a clonal mode of reproduction in a population of infected human immunodeficiency virus-positive patients.
Pujol, C., Reynes, J., François Renaud, A., Michel Raymond, A., Tibayrenc, M., Ayala, F. J., Janbon, F., Mallié, M., & Bastide, J.-M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9456 · Cited by 174
Rapid, Transient Fluconazole Resistance in Candida albicans Is Associated with Increased mRNA Levels of CDR
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
Self-citation
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Löffler, J., Kelly, S. L., Hebart, H. F., Schumacher, U., Lass‐Flörl, C., & Einsele, H. (1997) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1997.tb12580.x · Cited by 159
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Marr, K. A., White, T. C., van Burik, J. H., & Bowden, R. A. (1997) · Clinical Infectious Diseases · doi:10.1086/515553 · Cited by 145
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Candida albicans gene encoding resistance to benomyl and methotrexate is a multidrug resistance gene
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High prevalence of antifungal resistance in Candida spp. from patients with AIDS
Law, D., Moore, C. B., Wardle, H. M., Ganguli, L. A., Keaney, M. G. L., & Denning, D. W. (1994) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/34.5.659 · Cited by 139
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Self-citation
Molecular analysis of cyp51 from fluconazole-resistant Candida albicans strains
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Self-citation
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LAI, M. H., & Kirsch, D. R. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.2.804 · Cited by 106
The Candida albicans CDR3 gene codes for an opaque-phase ABC transporter
Balan, I., Alarco, A., & Raymond, M. (1997) · Journal of Bacteriology · doi:10.1128/jb.179.23.7210-7218.1997 · Cited by 102
Correlation between rhodamine 123 accumulation and azole sensitivity in Candida species: possible role for drug efflux in drug resistance
Clark, F. S., Parkinson, T., Hitchcock, C. A., & Gow, N. A. R. (1996) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.40.2.419 · Cited by 101
Sequence of theCandida albicansgene encoding actin
Losberger, C., & Ernst, J. F. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.22.9488 · Cited by 93
Emergence of Resistance of Candida albicans to Clotrimazole in Human Immunodeficiency Virus-Infected Children: In Vitro and Clinical Correlations
Pelletier, R., Peter, J., Antin, C., Gonzalez, C. E., Wood, L. V., & Walsh, T. J. (2000) · Journal of Clinical Microbiology · doi:10.1128/jcm.38.4.1563-1568.2000 · Cited by 90
Multidrug resistance in Candida albicans: disruption of the BENr gene
Goldway, M., Teff, D., Schmidt, R., Oppenheim, A., & Koltin, Y. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.2.422 · Cited by 89
Transcriptional Analyses of Antifungal Drug Resistance in Candida albicans
Lyons, C. N., & White, T. C. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.9.2296-2303.2000 · Cited by 79
Self-citation
Mitotic recombination in Candida albicans: Recessive lethal alleles linked to a gene required for methionine biosynthesis
Whelan, W. L., & Soll, D. R. (1982) · Molecular and General Genetics MGG · doi:10.1007/bf00332632 · Cited by 77
A fourth gene from the Candida albicans CDR family of ABC transporters
Franz, R., Michel, S., & Morschhäuser, J. (1998) · Gene · doi:10.1016/s0378-1119(98)00412-0 · Cited by 64
Completion of the IS map in E. coli: IS186 positions on the E. coli K12 chromosome
Birkenbihl, R. P., & Vielmetter, W. (1991) · Molecular and General Genetics MGG · doi:10.1007/bf00273620 · Cited by 33
Myelofibrosis Complicated by Infection Due toCandida albicans: Emergence of Resistance to Antifungal Agents During Therapy
Mori, T., Matsumura, M., Kanamaru, Y., MIYANO, S., Hishikawa, T., Irie, S., Oshimi, K., Saikawa, T., & Oguri, T. (1997) · Clinical Infectious Diseases · doi:10.1086/516987 · Cited by 28
A new member of YER057c family in Trypanosoma cruzi is adjacent to an ABC-transporter
Robello, C., Dallagiovanna, B., Engel, J. C., Gamarro, F., & Castanys, S. (1998) · Gene · doi:10.1016/s0378-1119(98)00439-9 · Cited by 12

Research works printed but not linked: 2

Holmberg, K., and D. A. Stevens. 1999. Resistance to antifungal drugs: current status and clinical implications. Curr. Opin. Anti-Infective Investig. Drugs1:306-317.
Odds F. C. 1988. Candida and Candidosis: a review and bibliography. Bailliere Tindall London United Kingdom.

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Authors: White, T. C., Holleman, S., Dy, F., Mirels, L. F., & Stevens, D. A.
Affiliations: Center for Infectious Disease Research (US)
Santa Clara Valley Medical Center (US)
Corresponding author: White, Theodore C.
ORCID: White, Theodore C.
Stevens, David A.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2002-06
Volume: 46
Issue: 6
Pages: 1704-1713
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.46.6.1704-1713.2002
PMC: PMC127245
OpenAlex: W2117461892
Cited by: 461
References: 42
Citations by year: 2026: 8 · 2025: 9 · 2024: 14 · 2023: 15 · 2022: 24 · 2021: 9 · 2020: 16 · 2019: 28 · 2018: 16 · 2017: 23 · 2016: 22 · 2015: 31 · 2014: 28 · 2013: 19 · 2012: 12
FWCI: 13.35
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Burroughs Wellcome Fund
M.J. Murdock Charitable Trust
National Institutes of Health
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 › Plant Science › Fungal Plant Pathogen Control
Keywords: Candida albicans, azole resistance, drug resistance mechanisms, ERG11 mutations, CDR1, CDR2, MDR1, efflux pump overexpression, cross-resistance, fluconazole, clotrimazole, itraconazole, ketoconazole, clinical isolates
MeSH terms: Antifungal Agents, Candida albicans, Candidiasis, DNA, Fungal, Drug Resistance, Microbial, Fungal Proteins, Microbial Sensitivity Tests, Phenotype, Polymorphism, Restriction Fragment Length, RNA, Fungal, Blotting, Southern, Blotting, Northern, DNA Probes, Gene Expression Regulation, Fungal, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, Genes, MDR, Reverse Transcriptase Polymerase Chain Reaction

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Resistance Mechanisms in Clinical Isolates of Candida albicans

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