Antifungal and sensitizing effect of cadinane-type sesquiterpenes from Heterotheca inuloides Cass. against azole-resistant Candida species.

AIMS: To evaluate the antifungal activity of sesquiterpenes from Heterotheca inuloides, estimate their sensitizing activity against resistant Candida glabrata and C. tropicalis, and elucidate the possible mechanisms of bioactivity through molecular docking.

METHODS AND

RESULTS

The MIC of sesquiterpenes, fluconazole (FLU), voriconazole (VOR), clotrimazole (CLO), or their combination was determined by broth microdilution method. Compounds 5 and 7 showed the best antifungal activity with MIC of 37.5 and 75.0 μg/mL in C. tropicalis and C. glabrata, respectively. On the other hand, the sesquiterpenes increased the effectiveness of FLU, VOR, and CLO. The most significant sensitization effects to FLU were observed when combined with compounds 4 and 5, which reduced the MIC by 8-fold (from 256 to 32 μg/mL) in C. tropicalis and 4-fold (from 256 to 64 μg/mL) in C. glabrata. For VOR, compounds 5 and 6 decreased the MIC up to 4-fold (from 8 to 2 μg/mL) in both fungal strains. Compound 6 also reduced the MIC of CLO by up to 8-fold (from 64 to 8 μg/mL) in C. tropicalis. Finally, all sesquiterpenes were found to interact with the lanosterol 14α-demethylase and CDR efflux pump.

CONCLUSIONS

Sesquiterpenes exhibited moderate antifungal activity against resistant C. glabrata and C. tropicalis. They enhanced the effectiveness of FLU, VOR, and CLO. According to molecular docking, the antifungal and resistance-sensitizing activity could be attributed to the inhibition of lanosterol 14α-demethylase and CDR efflux pump, respectively.