Resumo

Candida albicans remains the most common fungal isolate recovered from blood, recent reports indicate a trend towards an increasing prevalence of infections caused by species of Candida other than C. albicans which are associated with a highly mortality rate. A principal factor in patients with serious underlying diseases is clinical resistance. Antifungal drug resistance is a prominent feature in the management of invasive mycoses, and its epidemiological characteristics continue to evolve. This scenario leads to seek for new candidates for antifungal drugs able to overcome the resistance issues of Candida species. Many reports have extensively shown that kaurene-type diterpenes exert several biological activities. One such kaurene-type diterpene, kaurenoic acid (KA), has been reported to have antimicrobial activity, including against Candida spp. The aim of current study was evaluate the potential antifungal of the natural diterpenoids KA, 14-hydroxy-kaurane and xylopic acid, and three known semi-synthetic derivatives of KA towards fluconazole-resistant C. parapsilosis using the broth microdilution susceptibility test (CLSI document M27-A3). Also, cytotoxic and genotoxic/mutagenic effects of tested compounds were evaluated in vitro (human lymphocytes) and in vivo (mice). After 24 h exposure, none of tested drugs (0.25-128 μg/mL) showed antifungal activity (MIC50 > 128 μg/mL), but when combined with fluconazole (2 µg/mL), only one KA derivative, 16α-methoxy-kaurenoic-methyl ester, was able to significantly interfere on candida growth (MIC50 < 0.25 μg/mL; ΣFICI < 0.03). Interestingly, in contrast to KA, none of the semi-synthetic and natural derivatives of KA were cytotoxic or genotoxic/mutagenic upon human or murine cells. These data reinforce that the antifungal studies with kaurane diterpenes should be stressed to access the structure–activity relationship of both therapeutical and toxicological activities.