Benzo[a]phenoxazine derivative C34 efficacy against fluconazole-resistant Candida spp.

Candida infections pose a significant health risk, prompting the search for new antifungal solutions due to the diminishing effectiveness of traditional drugs. Benzo[a]phenoxazine derivatives, described to have antimicrobial activity, are promising candidates. This study assessed the antifungal efficacy of five benzo[a]phenoxazine derivatives against Candida species for an effective antifungal strategy. The antifungal activity of various compounds against C. albicans, C. auris, C. glabrata C. parapsilosis, C. krusei and C. bracarensis was assessed using the yeast EUCAST protocol. C34, the most effective compound, was encapsulated in DODAB:MO liposomes. Antifungal efficacy, adhesion, and filamentation effects were compared for free and encapsulated C34. Cytotoxicity was determined via the MTT assay in the J774A.1 macrophage-like cell line, which was also employed to assess macrophage yeast killing in the presence of C34. The MIC values ranged from 3.75 to 60 μM, with C34 emerging as the most effective compound against all tested species/strains, specifically against fluconazole-resistant strains. Encapsulation in DODAB:MO liposomes improved C34's antifungal activity for most species, reducing MIC values. Both free and encapsulated C34 effectively reduced Candida adhesion and filamentation. Cytotoxicity assessment allowed the identification of a non-cytotoxic concentration of C34 that significantly enhanced macrophage activity against C. albicans. C34 displayed potent antifungal activity against various strains, including fluconazole-resistant ones as C. auris. It reduced key virulence factors, such as adhesion and filamentation, and enhanced macrophage-mediated clearance, making it a compound of interest for further development as a potential therapeutic option.