Evaluation of the efficacy of heat shock protein inhibitors and antifungal drug combinations against Candida spp.

Abstract

Candida species are one of the predominant causes of fungal infections and show drug-resistant infections in immune-compromised individuals. Simultaneous targeting of existing antifungal drugs with heat shock protein 90 (Hsp90) inhibitors may be an approach that increases the efficacy of antifungal drugs. Also, since most of the patients at risk for invasive fungal infections use these anticancer or immunosuppressive drugs, synergistic interaction in combination treatment can reduce the dose of antifungal drugs and create an alternative for the toxicity problem. In this study, in vitro efficacy of commonly used antifungals (amphotericin B, caspofungin, itraconazole, voriconazole, and fluconazole) in combination with four heat shock protein inhibitors geldanamycin, 17-allylamino-17-demethoxygeldanamycin, radicicol, and novobiocin against 30 clinical Candida isolates (C. albicansn = 13, C. krusein = 7, and C. glabratan = 10) were evaluated by time kill and checkerboard methods. The significant synergistic interaction determined especially in the combinations of geldanamycin with antifungal drugs suggests that substances with inhibitory effects on Hsp90 increase the effectiveness of antifungals or reduce the antifungal resistance. Although Hsp90 inhibitors alone did not have any significant antifungal activity, they did not show adverse interactions in combination with antifungals, and at some concentrations, they increased the effectiveness of the antifungals. These in vitro results have been found promising for the development of new therapeutic approaches in the treatment of invasive fungal infections. However, detailed studies are needed.