Molecular Mechanisms of Primary Resistance to Flucytosine in Candida albicans

Hope, William W.; Tabernero, Lydia; Denning, David W.; Anderson, Michael J.

doi:10.1128/aac.48.11.4377-4386.2004

Cited by 161Antifungal resistance and susceptibilityFungal and yeast genetics researchBiochemical and Molecular Research

Molecular Mechanisms of Primary Resistance to Flucytosine in Candida albicans

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Hope, William W., Tabernero, Lydia, Denning, David W., Anderson, Michael J.·2004·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.48.11.4377-4386.2004PMC PMC525410

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Abstract

Primary resistance in Candida albicans to flucytosine (5-FC) was investigated in 25 strains by identifying and sequencing the genes FCA1, FUR1, FCY21, and FCY22, which code for cytosine deaminase, uracil phosphoribosyltransferase (UPRT), and two purine-cytosine permeases, respectively. These proteins are involved in pyrimidine salvage and 5-FC metabolism. An association between a polymorphic nucleotide and resistance to 5-FC was found within FUR1 where the substitution of cytidylate for thymidylate at nucleotide position 301 results in the replacement of arginine with cysteine at amino acid position 101 in UPRT. Isolates that are homozygous for this mutation display increased levels of resistance to 5-FC, whereas heterozygous isolates have reduced susceptibility. Three-dimensional protein modeling of UPRT suggests that the Arg101Cys mutation disturbs the quaternary structure of the enzyme, which is postulated to compromise optimal enzyme activity. A single resistant isolate, lacking the above polymorphism in FUR1, has a homozygous polymorphism in FCA1 that results in a glycine-to-aspartate substitution at position 28 in cytosine deaminase.

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Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes.
“Decreased susceptibility towards flucytosine has been associated with point mutations in FCY1, FCY2, and FUR1 genes and the deletion of FPS1 and FPS2 genes [36,114,115,116,117].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [114]
Such flucytosine resistance mechanisms have been observed in C. albicans, C. lusitaniae, and C. glabrata.
“Such resistance mechanisms have been observed in C. albicans [114], C. lusitaniae [115], and C. glabrata [116,117].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [114]

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Authors: Hope, W. W., Tabernero, L., Denning, D. W., & Anderson, M. J.
Affiliations: National Institutes of Health (US)
University of Manchester (GB)
ORCID: Hope, William W.
Tabernero, Lydia
Denning, David W.
Anderson, Michael J.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2004-11
Volume: 48
Issue: 11
Pages: 4377-4386
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.48.11.4377-4386.2004
PMC: PMC525410
OpenAlex: W2124393272
Cited by: 160
References: 33
Citations by year: 2026: 7 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 6 · 2021: 13 · 2020: 10 · 2019: 5 · 2018: 5 · 2017: 13 · 2016: 7 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 8
FWCI: 3.19
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords: flucytosine resistance, Candida albicans, uracil phosphoribosyltransferase, cytosine deaminase, pyrimidine salvage pathway, single nucleotide polymorphisms, quaternary structure, antifungal resistance
MeSH terms: Amino Acid Sequence, Antifungal Agents, Antimetabolites, Candida albicans, DNA, Fungal, Flucytosine, Fluorouracil, Genes, Fungal, Microbial Sensitivity Tests, Models, Molecular, Molecular Sequence Data, Pentosyltransferases, Polymorphism, Genetic, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal, Membrane Transport Proteins, Saccharomyces cerevisiae Proteins, Nucleobase Transport Proteins, Cytosine Deaminase

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Molecular Mechanisms of Primary Resistance to Flucytosine in Candida albicans

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