The most important challenges for the modern antifungal chemotherapy are: a rapidly growing number of cases of fungal disseminated infections in immunocompromised patients, a very limited repertoire of available effective antifungal chemotherapeutics to cure such diseases and an emerging problem of fungal resistance, especially of the multidrug character. Our research activity has been for recent years aimed at search for novel targets for antifungal chemotherapy and new antifungal drug candidates, demonstrating high activity against multidrug-resistant (MDR) fungal cells. In the present studies we compared the in vitro growth-inhibitory activity of several antifungal drugs, including ketoconazole, fluconazole, clotrimazole, voriconazole, Amphotericin B and 5-fluorocytosine, against sensitive and multidrug-resistant Candida albicans clinical isolates, as well as against model Saccharomyces cerevisiae strains harbouring or lacking C. albicans genes, encoding particular drug-effluxing membrane proteins. Relative affinity of antifungal drugs to the main C. albicans drug transporters, CaCdr1p and CaCdr2p, was determined using a competitive fluorescent assay. In parallel studies, the same methodology was applied for several potential antifungal drugs having amino acid or peptide structure.

Our results show that presence and activity of multidrug transporters: CaCdr1p, CaCdr2p or CaMdr1p, makes fungal cells cross-resistant to all tested azole and triazole antifungal agents, including the newest, second-generation triazole derivative - voriconazole. Voriconazole and other antifungal azole and triazole derivatives were shown to compete effectively with the fluorescent probe, Rhodamine 6G, for the binding sites in CaCdr1p and CaCdr2p. On the other hand, the MDR cells did not demonstrate resistance to Amphotericin B and 5-fluorocytosine. Finally, we found that presence of CaCdr1p or CaCdr2p made the fungal cells more susceptible to the action of peptidic antifungal agents: nikkomycin, FMDP-peptides and oxalysyl peptides and to some antifungal amino acids. The results of our comparative studies allowed to formulate some general conclusions concerning novel strategies overcoming fungal MDR.

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