Leishmanicidal mechanism of sertraline

42 p.-8 fig. Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against Leishmania share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in Leishmania were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on Leishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in L. infantum promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as shortage of intracellular amino acids used as metabolic fuel by Leishmania Sertraline killed Leishmania through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy. This work was supported by grants of the Fondo de Investigaciones Sanitarias-ISCIII-FEDER (PI12-02706), and (RD16/0027/0010, Red de Enfermedades Tropicales, subprogram RETICS del Plan Estatal de I+D+i (2013-2016) co-financed with FEDER funds, SAF2015-65740-R, and CSIC PIE 201620E038 to L. R., São Paulo State Research Foundation (FAPESP 2015/23403-9 to A. G.T.); EADS-CASA/ Brazilian Air Force (FAB) mobility program to M.L.L., and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) to M.L.L.