Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter

Article Article scientifique Article Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter eng 2003 author Noël Thierry author François Fabienne author Paumard Patrick 548064 author Chastin Christiane author Brèthes Daniel author Villard Jean 29595 1275-1284 10.1128/aac.47.4.1275-1284.2003 12654658 0066-4804 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC152504/ 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 micro g/ml) and susceptible to fluconazole (0.5 < MIC < 2 micro g/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 [(14)C]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. Antifungal Agents/pharmacology Biological Transport Candida/drug effects Drug Resistance Fungal Fluconazole/pharmacokinetics/pharmacology Flucytosine/pharmacology Humans Phenotype Dewey 616 56 Département de médecine 221 false 298 Transplantation immunologie et osteoimmunologie 561 Antimicrobial Agents and Chemotherapy 47 4 9c8b7c66-a85b-42d2-aed0-b6bb06c0da17 Article (Published version) Public Antimicrobial-Agents-and-Chemotherapy-2003-Noël-1275.full.pdf 180723 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter	Antimicrobial Agents and Chemotherapy			2003	191	257

Archive ouverte UNIGE

Paumard, Patrick