Pentamidine antagonizes the benznidazole's effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-Trypanosoma cruzi target.

VERONICA SEGUEL; LORENA CASTRO; CHANTAL REIGADA; LEONEL CORTÉS; MARÍA V DÍAZ; MARIANA R MIRANDA; CLAUDIO A PEREIRA; CAROLINA CAMPOS-ESTRADA; JUAN D MAYA; ANTONIO MORELLO; ULRIKE KEMMERLING; LOPEZ MUÑOZ RA

EXPERIMENTAL PARASITOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2016

0014-4894

Benznidazole is the first-line drug used in treating Chagas disease, which is caused by the parasite Trypanosoma cruzi (T. cruzi). However, benznidazole has limited efficacy and several adverse reactions. Pentamidine is an antiprotozoal drug used in the treatment of leishmaniasis and African trypanosomiasis.In T. cruzi, pentamidine blocks the transport of putrescine, a precursor of trypanothione, which constitutes an essential molecule in the resistance of T. cruzi to benznidazole. In the present study, we describe the effect of the combination of benznidazole and pentamidine on isolated parasites,mammalian cells and in mice infected with T. cruzi. In isolated trypomastigotes, we performed a dosematrix scheme of combinations, where pentamidine antagonized the effect of benznidazole, mainly at concentrations below the EC50 of pentamidine. In T. cruzi-infected mammalian cells, pentamidine reversed the effect of benznidazole (measured by qPCR). In comparison, in infected BALB/c mice, pentamidine failed to get synergy with benznidazole, measured on mice survival, parasitemia and amastigote nest quantification. To further explain the in vitro antagonism, we explored whether pentamidine affects intracellular trypanothione levels, however, pentamidine produced no change in trypanothione concentrations.Finally, the T. cruzi polyamine permease (TcPAT12) was overexpressed in epimastigotes,