Antifungal Action of Valencene and Nootkatone Compounds in Association with Fluconazole and Their Mechanism of Action Against Candida spp. and Pichia kudriavzevii Strains.

Abstract

Candidemia is a public health challenge as it causes thousands of annual deaths and combating it has become difficult due to the development of resistance in Candida spp. Compounds derived from natural products may counter this resistance. Therefore, we evaluate the intrinsic and combined antifungal activity of valencene and nootkatone compounds and their possible mechanism of action against Candida spp. Using the microdilution method, the antifungal effect of sesquiterpenes and their combination with fluconazole was determined. The results comprised the yeast growth curve and its 50% Inhibitory Concentration (IC₅₀). They showed that the compounds alone inhibited microbial growth at a concentration of 1024 µg/mL for valencene being able to kill the fungus Pichia kudriavzevii (Candida krusei), for nootkatone the inhibition occurred at 512 µg/mL and was able to kill the species P. kudriavzevii and Candida tropicalis. Combined with the antifungal, the inhibition occurred at low concentrations (2 and 4 µg/mL) against all strains except P. kudriavzevii, which the combination with nootkatone inhibited at 512 µg/mL. The IC₅₀ revealed inhibition of the strains at higher concentrations in the compounds and fluconazole alone compared to the combination concentrations. In addition, both compounds acted through the production of reactive oxygen species, helping the antifungal against C. albicans and P. kudriavzevii, contributing minimally to compromising membrane viability. Thus, the compounds show promise for combined activity with fluconazole.