Miltefosine and benznidazole combination improve anti-Trypanosoma cruzi in vitro and in vivo efficacy

BISIO, MARGARITA MARÍA CATALINA; SOLANA, MARÍA ELISA; GULIN, JULIÁN ERNESTO NICOLÁS; ALTCHEH, JAIME; ROCCO, DANIELA MARISA; GARCÍA-BOURNISSEN, FACUNDO

Frontiers In Cellular and Infection Microbiology

Frontiers

Año: 2022 vol. 12

Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic alkylphospholipid initially developed for breast cancer and repositioned for leishmaniasis, is a promising candidate against Trypanosoma cruzi infection. This study evaluates the efficacy of MLT as a monodrug and combined with benznidazole (BZ) in both in vitro and in vivo models of infection with T. cruzi(VD strain, DTU TcVI). MLT exhibitedin vitro activity on amastigotes and trypomastigotes with values of IC50 =0.51 µM (0.48 µM; 0,55 µM) and LC50 = 31.17 µM (29.56 µM; 32.87 µM), respectively. Druginteraction was studied with the fixed-ration method. The sum of the fractional inhibitory concentrations (SFICs) resulted in∑FIC= 0.45 for trypomastigotes and∑FIC= 0.71 for amastigotes, suggestingin vitro synergistic and additive effects, respectively. No cytotoxic effects on host cells were observed. MLT efficacy was also evaluated in a murine model of acute infection alone or combined with BZ. Treatment was well tolerated with few adverse effects, and all treated animals displayed significantly lower mean peak parasitemia and mortality than infected non-treated controls (p