Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 62, Issue 12, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01928-18
Keywords
Leishmania; antidepressant; bioenergetics; drug repurposing; metabolomics; sertraline
Categories
Funding
- Fondo de Investigaciones Sanitarias-ISCIII-FEDER [PI12-02706, RD16/0027/0010]
- Red de Enfermedades Tropicales, subprogram RETICS del Plan Estatal de I + D + i
- FEDER funds [SAF2015-65740-R]
- FEDER funds (CSIC grant) [PIE 201620E038]
- Sao Paulo State Research Foundation [FAPESP 2015/23403-9]
- EADS-CASA/Brazilian Air Force (FAB) mobility program
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
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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 the 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 a 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.
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