Molecular mechanisms of primary resistance to flucytosine in Candida albicans

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Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
08:45

Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance

Published on: December 28, 2017

William W Hope1, Lydia Tabernero, David W Denning

  • 1Immunocompromised Host Section POB, NCI, NIH CRC, Room 1-5700, 10 Center Dr., MSC 1100, Bethesda, MD 20892-1100, USA. hopew@mail.nih.gov

Antimicrobial Agents and Chemotherapy
|October 27, 2004
PubMed

Insights

Primary resistance to flucytosine (5-FC) in Candida albicans is linked to specific gene mutations. A key mutation in the FUR1 gene impacts uracil phosphoribosyltransferase, affecting drug metabolism and resistance levels.

Area of Science:

  • Mycology
  • Molecular Biology
  • Antimicrobial Resistance

Background:

  • Candida albicans is a common fungal pathogen.
  • Flucytosine (5-FC) is an antifungal drug used to treat candidiasis.
  • Understanding resistance mechanisms is crucial for effective treatment.

Purpose of the Study:

  • To investigate the genetic basis of primary resistance to flucytosine in Candida albicans.
  • To identify specific gene mutations associated with flucytosine resistance.

Main Methods:

  • Sequencing of genes FCA1, FUR1, FCY21, and FCY22 in 25 Candida albicans strains.
  • Analysis of gene polymorphisms and their association with flucytosine resistance.
  • Three-dimensional protein modeling of the uracil phosphoribosyltransferase (UPRT) enzyme.

Main Results:

  • A specific mutation in the FUR1 gene (Arg101Cys in UPRT) was associated with increased flucytosine resistance in homozygous isolates.
  • Heterozygous isolates with this mutation showed reduced susceptibility.
  • A separate mutation in FCA1 was identified in one resistant isolate.

Conclusions:

  • Genetic variations in FUR1 and FCA1 play a significant role in primary flucytosine resistance in Candida albicans.
  • The Arg101Cys mutation in UPRT likely compromises enzyme activity, leading to resistance.
  • Further research into these genetic determinants can inform antifungal drug development and resistance management strategies.

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