Title: Synergism between Fluconazole and Terminalia catappa Extract and its Use in the Treatment of Candida-infected Tenebrio molitor Larvae / Título: Sinergismo entre Fluconazol e o Extrato de Terminalia catappa e seu uso no tratamento de larvas de Tenebrio molitor infectadas com Candida

The increase of Candida infections in the last few decades is alarming and the resistance development to antifungals, especially fluconazole, the most widely used drug for treatment, enhances the importance of these infections. Thus, identifying new substances and provide the pharmaceutical industry with the most effective drugs is imperative. Goals were to show the antifungal, anti-biofilm, and synergistic actions between fluconazole (FLZ) and hydroalcoholic extract of Terminalia catappa (TcHE) against Candida vaginal isolates. TcHE was analyzed for anti-Candida activity by agar diffusion and microdilutions assays. Totoxicity was evaluated by the hemolytic test and in larvae of Tenebrio molitor. The effect of TcHE on Candida cells was evaluated by flow cytometry analysis and interference of TcHE on biofilms by MTT assay. In vivo Candida infection and treatment with TcHE was analysed in T. molitor larvae. TcHE showed antifungal activity against all strains tested. The extract was not cytotoxic among concentrations of 3 to 100 mg/mL. Moreover, combinations of TcHE with FLZ have considerably increased the anti-yeast activity (FICI ? 0.5). Our findings indicated that TcHE promoted cell membrane instability probably causing plasma membrane damage in C. albicans, resulting in increased cell membrane permeability. These results could also explain the synergistic activity observed between TcHE and fluconazole. TcHE exhibited anti-biofilm properties against C. albicans strains. The antifungal activity and the low cytotoxic potential demonstrated by TcHE reveal that it is promising for development as a new antimycotic