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Antimicrobial Agents and Chemotherapy, November 2004, p. 4377-4386, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4377-4386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Mechanisms of Primary Resistance to Flucytosine in Candida albicans

William W. Hope,1* Lydia Tabernero,2 David W. Denning,1 and Michael J. Anderson1

School of Medicine,1 Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom2

Received 18 February 2004/ Returned for modification 7 April 2004/ Accepted 21 July 2004

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.

* Corresponding author. Present address: Immunocompromised Host Section POB, NCI, NIH CRC, Room 1-5700, 10 Center Dr., MSC 1100, Bethesda, MD 20892-1100. Phone: (301) 451-7035. Fax: (301) 480-2308. E-mail: hopew{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4377-4386, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4377-4386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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