Cited by 292Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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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White, T C·1997·Antimicrobial Agents and Chemotherapy

Abstract

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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Crossref · 10.1128/aac.41.7.1488

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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).”

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Authors
White, T. C.
Affiliations
Center for Infectious Disease Research (US)
Corresponding author
White, T C
Venue
Antimicrobial Agents and Chemotherapy
Published
1997-07
Volume
41
Issue
7
Pages
1488-1494
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
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
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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