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Molecular basis of the leishmanicidal activity of the antidepressant sertraline as a drug repurposing candidate

Other TitlesLeishmanicidal mechanism of sertraline
AuthorsLima, Marta L.; Abengozar, M. A. ; Nácher-Vázquez, Montserrat ; Martinez-Alcazar, Maria P.; Barbas, Coral; Tempone, Andre G.; López-Gonzálvez, Ángeles; Rivas, Luis
Drug repurposing
Issue Date8-Oct-2018
PublisherAmerican Society for Microbiology
CitationAntimicrob Agents Chemother pii: AAC.01928-18 (2018)
AbstractDrug 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.
Description42 p.-8 fig.
Publisher version (URL)https://doi.org/10.1128/AAC.01928-18
Appears in Collections:(CIB) Artículos
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