2-aryloxazolines inhibit Candida clinical isolates growth and morphogenesis of Candida albicans and Candida tropicalis

Abstract

New antifungal molecules are being researched addressing new targets and mechanisms of action. Therefore, the present study aimed to evaluate the antifungal activity of 2-aryloxazoline derivatives (4i and 9i) on Candida clinical isolates and on morphogenesis of competent-filament species. Both compounds inhibited Candida spp. growth at concentrations ≤0.03–2 μg/mL, including less susceptible and resistant isolates to standard antifungals. However, neither fungicidal effect of compounds nor synergistic/antagonistic interactions in combination with antifungals were observed. On the other hand, C. albicans treated with 2-aryloxazoline exhibited some ultrastructural changes such as the integrity loss of the plasma membrane and cell wall. In C. albicans, the proteinase activity was reduced after treatment with high concentrations of 2-aryloxazoline, but this inhibition was not observed in C. tropicalis. The compounds inhibited up to 50% of the total biomass of C. albicans and C. tropicalis biofilms but did not inhibit the metabolic activity. Additionally, 2-aryloxazolines caused a dose-dependent reduction in the pseudohyphae/hyphae formation of both Candida species (C. albicans and C. tropicalis) in RPMI medium and other filament-inducing media. Notably, the compounds caused a total inhibition of pseudohyphae/hyphae formation in Spider broth, a partial inhibition in Lee medium, and no inhibition in SM supplemented with N-acetylglucosamine. This effect on the yeast-hyphae transition was associated with blockage of cAMP and MAPK pathways due to the gene downregulation of the transcription factors TEC1, EFG1, and CEK1 in 4i-treated C. albicans cells. In this regard, the adhesins (HWP1 and ALS3) and candidalysin (ECE1) genes were also downregulated as a result of the interference of compounds on the filamentation signaling pathways. Therefore, 2-aryloxazolines showed promising results inhibiting Candida growth and morphogenesis; however, other approaches should be carried out to better elucidate other possible mechanisms of action.