In Vitro Evaluation of 5-Fluorouridine as an Adjuvant to Antifungal Drugs and Molecular Insights into Resistance to This Compound in Candida Species

This study evaluated the in vitro interaction of 5-fluorouridine (5-FUrd) with antifungal drugs and examined the role of efflux pumps in 5-FUrd resistance. Eleven reference <i>Candida</i> strains and twenty-three clinical <i>C. albicans</i> isolates from gynecological patients were tested. The antifungal activity of 5-FUrd alone and in combination with amphotericin B, fluconazole, voriconazole, caspofungin, and flucytosine was assessed using the checkerboard microdilution method. Efflux pump activity was evaluated using two inhibitors: carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and verapamil. 5-FUrd exhibited antifungal activity against both the reference and clinical <i>Candida</i> strains, with MIC values ranging from 0.1 µg/mL to 409.6 µg/mL. The checkerboard assays revealed primarily no interactions in the reference <i>Candida</i> strains, whereas the reference <i>C. albicans</i> and clinical <i>C. albicans</i> isolates showed notable synergy between 5-FUrd and fluconazole, voriconazole, or caspofungin. The efflux pump inhibitors reduced the MICs of 5-FUrd in the resistant strains of <i>C. lusitaniae</i>, <i>C. kefyr</i>, and particularly <i>C. krusei</i>, suggesting efflux-mediated resistance mechanisms. This study highlights the potential of 5-FUrd, alone or combined with azoles or caspofungin, as an adjunct therapy against <i>Candida</i> infections. It also suggests that reduced susceptibility may be linked to efflux pump activity in certain strains.