2024-03-28T19:24:51Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1711672021-12-27T16:44:10Zcom_10261_86com_10261_1col_10261_339
Lima, Marta L.
Abengozar, M. A.
Nácher-Vázquez, Montserrat
Martinez-Alcazar, Maria P.
Barbas, Coral
Tempone, Andre G.
López-Gonzálvez, Ángeles
Rivas, Luis
2018-10-17T11:28:15Z
2018-10-17T11:28:15Z
2018-10-08
Antimicrob Agents Chemother pii: AAC.01928-18 (2018)
0066-4804
http://hdl.handle.net/10261/171167
10.1128/AAC.01928-18
1098-6596
http://dx.doi.org/10.13039/501100003339
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100004587
30297370
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 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.
eng
openAccess
Sertraline
Drug repurposing
Metabolomics
Molecular basis of the leishmanicidal activity of the antidepressant sertraline as a drug repurposing candidate
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