Journal
EXPERIMENTAL PARASITOLOGY
Volume 171, Issue -, Pages 23-32Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.exppara.2016.10.007
Keywords
Trypanosoma cruzi; Chagas disease; Pentamidine; Benznidazole; Polyamine transport
Categories
Funding
- Consejo Nacional de Ciencia y Tecnologia (CONICYT-Chile) [FONDECYT: 11110182, 1160807, 1120230, 1130189]
- Vicerrectoria de Investigacion y Desarrollo, Universidad de Chile [U-INICIA 11/07]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET, PIP) [2010-0685, 2011-0263]
- Agencia Nacional de Promocion Cientifica y Tecnologica (FONCYT, PICT) [2012-0559, 2013-2218]
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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 dose matrix 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, showing that pentamidine has the same trypanocidal effect, independently of transporter expression levels. These results suggest that, in spite of the high potency in the putrescine transport blockade, TcPAT12 permease is not the main target of pentamidine, and could explain the lack of synergism between pentamidine and benznidazole. (C) 2016 Elsevier Inc. All rights reserved.
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