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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate

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Author(s):
Lima, Marta L. [1, 2, 3] ; Abengozar, Maria A. [2] ; Nacher-Vazquez, Montserrat [2] ; Martinez-Alcazar, Maria P. [3] ; Barbas, Coral [3] ; Tempone, Andre G. [1] ; Lopez-Gonzalvez, Angeles [3] ; Rivas, Luis [2]
Total Authors: 8
Affiliation:
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Sao Paulo, SP - Brazil
[2] CSIC, CIB, Madrid - Spain
[3] Univ CEU San Pablo, Fac Farm, Ctr Metab & Bioanal CEMBIO, Madrid - Spain
Total Affiliations: 3
Document type: Journal article
Source: Antimicrobial Agents and Chemotherapy; v. 62, n. 12 DEC 2018.
Web of Science Citations: 3
Abstract

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. (AU)

FAPESP's process: 15/23403-9 - Rational pre-clinical study of new drug candidates against neglected protozoan diseases using pharmacokinetic approaches
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants