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Antimicrobial Agents and Chemotherapy, April 2003, p. 1275-1284, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1275-1284.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Flucytosine-Fluconazole Cross-Resistance in Purine-Cytosine Permease-Deficient Candida lusitaniae Clinical Isolates: Indirect Evidence of a Fluconazole Uptake Transporter

Laboratoire des Sciences Végétales, Faculté de Pharmacie, Université René Descartes-Paris 5, Paris 75006,¹ Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Bordeaux 33077 Cedex, France²

Received 24 July 2002/ Returned for modification 15 October 2002/ Accepted 30 December 2002

An unusual interaction between flucytosine and fluconazole was observed when a collection of 60 Candida lusitaniae clinical isolates was screened for cross-resistance. Among eight isolates resistant to flucytosine (MIC 128 µg/ml) and susceptible to fluconazole (0.5 < MIC < 2 µg/ml), four became flucytosine-fluconazole cross resistant when both antifungals were used simultaneously. Fluconazole resistance occurred only in the presence of high flucytosine concentrations, and the higher the fluconazole concentration used, the greater the flucytosine concentration necessary to trigger the cross-resistance. When the flucytosine- and fluconazole-resistant cells were grown in the presence of fluconazole alone, the cells reversed to fluconazole susceptibility. Genetic analyses of the progeny from crosses between resistant and sensitive isolates showed that resistance to flucytosine was derived from a recessive mutation in a single gene, whereas cross-resistance to fluconazole seemed to vary like a quantitative trait. We further demonstrated that the four clinical isolates were susceptible to 5-fluorouracil and that cytosine deaminase activity was unaffected. Kinetic transport studies with [¹⁴C]flucytosine showed that flucytosine resistance was due to a defect in the purine-cytosine permease. Our hypothesis was that extracellular flucytosine would subsequently behave as a competitive inhibitor of fluconazole uptake transport. Finally, in vitro selection of spontaneous and induced mutants indicated that such a cross-resistance mechanism could also affect other Candida species, including C. albicans, C. tropicalis, and C. glabrata. This is the first report of a putative fluconazole uptake transporter in Candida species and of a possible resistance mechanism associated with a deficiency in the uptake of this drug.

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