| Congresso Brasileiro de Microbiologia 2023 | Resumo: 562-1 | ||||
Resumo:Cryptococcosis therapy is often limited by toxicity problems, antifungal tolerance, and high costs. Studies approaching chalcogen compounds, especially those containing selenium, have shown promising antifungal activity against pathogenic species. This work aimed to evaluate the in vitro and in vivo antifungal potential of an organoselenium compound against Cryptococcus neoformans.The lead compound LQA_78 had inhibitory and fungicidal activities against clinical isolates of C. neoformans (n=9) at 16 and 32 µg/mL, respectively. LQA_78 inhibited in vitro the virulent morphotypes (enlarged capsule yeasts and Titan cells) and fungal melanization by reducing the laccase activity in yeasts and in culture supernatant. LQA_78 showed to be safe for up to 46.5 mg/kg in Galleria mellonella model, and at 40 mg/kg, it was able to significantly reduce the larval fungal load and inhibit the formation of Titan cells and capsular thickness of the yeasts in the hemolymph. However, the compound has low solubility at concentrations ≤ 5% of DMSO in aqueous medium; in order to solve these problems and given the chemical characteristics of the molecule, LQA-78 was incorporated in a copolymeric (poly(D,L-lactide-co-glycolide) acid (PLGA)) nanocarrier. The PLGA platform was stable for 30 days at room temperature without significant changes in the polydispersity index (0.180 ± 0.087) and zeta potential (-34.2 mV ± 2.34). In addition, the nanocarrier was able to encapsulate 92.5% of LQA_78. The PLGA+LQA_78 formulation inhibited the fungal growth of C. neoformans at a concentration equal to its free form (8 µg/mL), while the unloaded PLGA formulation (without LQA_78) did not interfere with fungal growth. In G. mellonella, neither PLGA formulations (unloaded and PLGA+LQA_78) were toxic to the larvae even at the highest tested dose (80mg/kg). In addition, the group infected and treated with PLGA+LQA_78 (20 and 40 mg/kg) showed a significant reduction in the fungal burden by almost 50% compared to the infected and untreated group. However, only treatment at the highest dose (40mg/kg) provided significant protection for infected larvae, with more than 40% of the population remaining alive on the last day of evaluation. In conclusion, LQA_78 displays fungicidal action in vivo and inhibits virulence factors of C. neoformans in vivo and in vitro. in addition, the PLGA nanocarrier with LQA_78 has been shown to be safe in G. mellonella and effective for use in the treatment of cryptococcosis. Our results highlight the potential use of LQA_78 as a lead molecule for developing novel pharmaceuticals for treating cryptococcosis. Palavras-chave: Cryptococcus, Galleria mellonella, nanoparticles, Organoselenium, Treatment Agência de fomento:FAPESP, CNPq, CAPES | |||||