CONICET | Buscador de Institutos y Recursos Humanos

In previous studies, 2´, 4´-dihydroxy-5´-(1´´´, 1´´´-dimethylallyl)-6-prenylpinocembrin (6PP), a prenylated flavonoid isolated from Dalea elegans roots, showed activity against multi-resistant Staphylococcus aureus and Candida albicans, as well as an uncoupling effect on mitochondria and anti-oxidant activity. The aim of this study was to evaluate the inhibitory effects of 6PP and fluconazole on the efflux of rhodamine 6G (Rh 6G) in azole-resistant C. albicans 12-99 (RCa) that expresses multidrug transporters Cdr1p, Cdr2p and Mdr1p. The effect of fluconazole and 6PP on Rh 6G efflux was assessed in both azole-sensitive and azole-resistant C. albicans. Between 1 and 1000 µM, 6PP inhibited rhodamine 6G efflux only in RCa in a concentration-dependent manner (IC50 =119 µM); a competitive effect was observed. It also showed selectivity of action in comparison with other flavanones (6-prenylpinocembrin, isolated from aerial parts of D. elegans, pinocembrin, naringenin and hesperetin, all at 250 µM). To check the possible implications of the inhibition of azole efflux on cell growth, antifungal assays were conducted. Minimal inhibitory concentration (MIC) values were 150 µM for 6PP and higher than 400 µM for Flz. The combination of both compounds at either inhibitory or subinhibitory concentrations was significantly more effective than each compound separately. MIC for Flz decreased by more than 400 times in the presence of 100 µM 6PP, reversing azole-resistance and giving values similar to those of azole-sensitive C. albicans. These data are consistent with a dual action of 6PP: direct antifungal effect on RCa and inhibition of azole transporters, which results in reversion of fluconazole resistance.

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