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Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate.
Antimicrob Agents Chemother. 2018 12; 62(12)AA

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.

Authors+Show Affiliations

Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain. Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain. Centre for Parasitology and Mycology, Institute Adolfo Lutz, São Paulo, São Paulo, Brazil.Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.Centre for Parasitology and Mycology, Institute Adolfo Lutz, São Paulo, São Paulo, Brazil.Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain alopgon@ceu.es luis.rivas@cib.csic.es.Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain alopgon@ceu.es luis.rivas@cib.csic.es.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30297370

Citation

Lima, Marta L., et al. "Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate." Antimicrobial Agents and Chemotherapy, vol. 62, no. 12, 2018.
Lima ML, Abengózar MA, Nácher-Vázquez M, et al. Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate. Antimicrob Agents Chemother. 2018;62(12).
Lima, M. L., Abengózar, M. A., Nácher-Vázquez, M., Martínez-Alcázar, M. P., Barbas, C., Tempone, A. G., López-Gonzálvez, Á., & Rivas, L. (2018). Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate. Antimicrobial Agents and Chemotherapy, 62(12). https://doi.org/10.1128/AAC.01928-18
Lima ML, et al. Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate. Antimicrob Agents Chemother. 2018;62(12) PubMed PMID: 30297370.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate. AU - Lima,Marta L, AU - Abengózar,María A, AU - Nácher-Vázquez,Montserrat, AU - Martínez-Alcázar,María P, AU - Barbas,Coral, AU - Tempone,Andre G, AU - López-Gonzálvez,Ángeles, AU - Rivas,Luis, Y1 - 2018/11/26/ PY - 2018/09/07/received PY - 2018/09/28/accepted PY - 2018/10/10/pubmed PY - 2019/10/12/medline PY - 2018/10/10/entrez KW - Leishmania KW - antidepressant KW - bioenergetics KW - drug repurposing KW - metabolomics KW - sertraline JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 62 IS - 12 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/30297370/Molecular_Basis_of_the_Leishmanicidal_Activity_of_the_Antidepressant_Sertraline_as_a_Drug_Repurposing_Candidate_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=30297370 DB - PRIME DP - Unbound Medicine ER -