Screening of drugs with potential antifungal activity for repurposing in the treatment of cryptococcosis.

Abstract

Current therapeutic alternatives for the treatment of cryptococcosis are scarce, highly toxic, expensive, and difficult to access. Therefore, the aim of this study was to evaluate the anticryptococcal potential of a collection of 27 drugs in vitro against several strains of Cryptococcus neoformans and Cryptococcus gattii. We investigated several parameters to evaluate the antifungal activity of the drugs: determination of minimum inhibitory concentration (MIC), combinatorial effects with fluconazole, kinetics of growth inhibition, post-antifungal effect (PAFE), and morphometric analyses at subinhibitory concentrations. Antiparasitics albendazole, fenbendazole, flubendazole, mebendazole, and antidepressants duloxetine and paroxetine showed antifungal activity with an MIC of 100 µmol l-1 or less for most strains tested. The results of the zero-interaction power model indicated additive effects for combination of fluconazole with drugs finasteride, hydroxyzine, and paroxetine. The combined treatments significantly improved the ability of fluconazole to kill C. neoformans ATCC H99. Same phenomenon occurred in the in vitro PAFE, as the combinations suppressed fungal growth more effectively than fluconazole alone. A significant reduction in capsule size was observed. Screening of the drug collection showed interesting results, with benzimidazoles antiparasitics and serotonin and norepinephrine reuptake inhibitors in foreground. Finasteride, hydroxyzine, and paroxetine significantly improved activity of fluconazole in vitro.