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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 62, n. 12 DEC 2018.
• Citações Web of Science: 5

Resumo

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)

• Processo FAPESP: 15/23403-9 - Estudo Pré-Clínico Racional de Novos Candidatos a Fármacos em Protozooses Negligenciadas Utilizando Abordagens Farmacocinéticas
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular