Atividade antifúngica de substâncias oxadiazóis contra gênero Candida e Cryptococcus

Abstract

Fungal infections affect immunocompromised and immunosuppressed patients and are caused by microorganisms under favorable conditions for their development, such as yeasts like Candida spp. and Cryptococcus spp.. However, the increasing reports of fungal resistance and the adverse effects associated with available antifungals highlight the need for new therapeutic alternatives. In this context, oxadiazole-derived compounds have been synthesized and investigated, demonstrating broad biological potential, including antiviral, antifungal, antibacterial, and antineoplastic activities. Therefore, the objective of this study was to evaluate the antifungal activity of fifteen oxadiazoles against Candida and Cryptococcus strains. The minimum inhibitory concentration (MIC) was determined by the microdilution technique, along with the minimum fungicidal concentration (MFC) and growth kinetics analysis to assess the action of the substances against fungi over time. A microcultivation assay in a humid chamber was also performed to verify the compounds' effects on the virulence structures of these yeasts. Antibiofilm activity was evaluated using the crystal violet technique. The mode of action on ergosterol and the quorum-sensing assay of farnesol in C. albicans were analyzed and quantified by High-Performance Liquid Chromatography (HPLC). Drug efflux analysis using a proton-motive force uncoupler was also performed. The molecular association study was conducted using Checkerboard technique. Among the molecules analyzed, JFOX-6 stood out by inhibiting all fungal strains, with MIC and MFC ranging from 256 to 1024 μg/mL under the evaluated conditions. In the growth kinetics assay, it exhibited fungistatic activity. It interfered with the production of virulence structures, significantly reducing the capsule thickness of Cryptococcus and inhibiting virulence and reproductive factors of Candida, such as pseudohyphae, blastoconidia, and chlamydoconidia. It also strongly interfered (2x MIC) with biofilm formation in the maturation and dispersion stages of C. neoformans, moderately with C. gattii, weakly with C. tropicalis, and completely inhibited C. albicans biofilm in the maturation stage. JFOX-6 interfered with ergosterol biosynthesis, and subinhibitory concentrations stimulated farnesol production in C. albicans. The resistance of these microorganisms to antifungals may be associated with efflux pump activity under the evaluated conditions. When JFOX-6 was combined with amphotericin B, the interaction was indifferent against Cryptococcus spp. and C. albicans. Considering the above, oxadiazoles appear to be promising antifungals in the study of opportunistic yeasts of clinical interest.