Antifungal and multidrug resistance modulatory effects of diterpenic and phenolic compounds

Azoles (fluconazole, itraconazole and ketoconazole) are among the few classes of antifungals available for the treatment of systemic yeast infections. Nowadays, due to the global AIDS pandemic and the use of immunosuppressive drugs in anticancer chemotherapy, the incidence of fungal infection as increased [1]. For these reasons, the resistance of yeasts to treatment is very common and the effectiveness of antifungal drugs is reduced by the activity of multidrug transporters from the ATP-binding cassette superfamily, such as Cdr1p and Cdr2p of the major human fungal pathogen Candida albicans. These proteins reduce intracellular drug concentration by actively extruding them out of cells. One of the strategies employed to overcome this type of resistance is the combination treatment with efflux pump inhibitors.

The aim of this work is to study the antifungal and multidrug resistance modulatory effect of diterpenic and phenolic compounds isolated from Euhorbia species in the model eucaryote Saccharomyces cerevisiae. Yeast strains either deleted in major endogenous multidrug ATP-binding cassette transporters PDR5, SNQ2 and YOR1 or specifically overproducing each pump separately were used. The effect of analysed compounds on the inhibition of heterologously overproduced Cdr1p of Candida albicans was also verified. Trifluoperazine was used as positive control exerting both growth inhibitory and modulatory activity. The analysed compounds exert weak antifungal activity and modulate to a different extent azole antifungal resistance mediated by Pdr5p, Snq2p, and Cdr1p.

Acknowledgements: The authors thank Dr. Teresa Vasconcelos (ISA, University of Lisbon, Portugal) for identification of the plant.

Reference: 1. Kolaczkowski, M. et al. (2003), Int. J. Antimicrobial Agents 22: 279–283.