Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate
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. Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the...
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container_title | Antimicrobial agents and chemotherapy |
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creator | Lima, Marta L. Abengózar, María A. Nácher-Vázquez, Montserrat Martínez-Alcázar, María P. Barbas, Coral Tempone, Andre G. López-Gonzálvez, Ángeles Rivas, Luis |
description | 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.
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. |
doi_str_mv | 10.1128/AAC.01928-18 |
format | Article |
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Leishmania
share this origin.
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.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01928-18</identifier><identifier>PMID: 29311090</identifier><identifier>PMID: 30297370</identifier><language>eng</language><publisher>1752 N St., N.W., Washington, DC: American Society for Microbiology</publisher><subject>Mechanisms of Action: Physiological Effects</subject><ispartof>Antimicrobial agents and chemotherapy, 2018-11, Vol.62 (12)</ispartof><rights>Copyright © 2018 American Society for Microbiology. 2018 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256786/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256786/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Lima, Marta L.</creatorcontrib><creatorcontrib>Abengózar, María A.</creatorcontrib><creatorcontrib>Nácher-Vázquez, Montserrat</creatorcontrib><creatorcontrib>Martínez-Alcázar, María P.</creatorcontrib><creatorcontrib>Barbas, Coral</creatorcontrib><creatorcontrib>Tempone, Andre G.</creatorcontrib><creatorcontrib>López-Gonzálvez, Ángeles</creatorcontrib><creatorcontrib>Rivas, Luis</creatorcontrib><title>Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate</title><title>Antimicrobial agents and chemotherapy</title><description>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.
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.</description><subject>Mechanisms of Action: Physiological Effects</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqljM1OhDAURhujcfBn5wPcF2BsmaGWjQmixoVu1D25wh24BlrSlknm7cVEF65dfflyTo4QV0qulcrMdVlWa6mKzKTKHIlEycKkOi_0sUik1DrdGrldibMQPuXy80KeilVWbNQiykS4FzdQMw_o4Q4DB3A7iD3BM3HoR7TccIsDlE3kPcfDLy5t5JYmTyGgjfBGPnoc2BJgAIR7P3fwStPsJxfYdlChbZdQpAtxssMh0OXPnovbx4f36imd5o-R2obsd6iePI_oD7VDrv8Sy33duX2ts1zfGL35d-ALS6to3Q</recordid><startdate>20181126</startdate><enddate>20181126</enddate><creator>Lima, Marta L.</creator><creator>Abengózar, María A.</creator><creator>Nácher-Vázquez, Montserrat</creator><creator>Martínez-Alcázar, María P.</creator><creator>Barbas, Coral</creator><creator>Tempone, Andre G.</creator><creator>López-Gonzálvez, Ángeles</creator><creator>Rivas, Luis</creator><general>American Society for Microbiology</general><scope>5PM</scope></search><sort><creationdate>20181126</creationdate><title>Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate</title><author>Lima, Marta L. ; Abengózar, María A. ; Nácher-Vázquez, Montserrat ; Martínez-Alcázar, María P. ; Barbas, Coral ; Tempone, Andre G. ; López-Gonzálvez, Ángeles ; Rivas, Luis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_62567863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Mechanisms of Action: Physiological Effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lima, Marta L.</creatorcontrib><creatorcontrib>Abengózar, María A.</creatorcontrib><creatorcontrib>Nácher-Vázquez, Montserrat</creatorcontrib><creatorcontrib>Martínez-Alcázar, María P.</creatorcontrib><creatorcontrib>Barbas, Coral</creatorcontrib><creatorcontrib>Tempone, Andre G.</creatorcontrib><creatorcontrib>López-Gonzálvez, Ángeles</creatorcontrib><creatorcontrib>Rivas, Luis</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lima, Marta L.</au><au>Abengózar, María A.</au><au>Nácher-Vázquez, Montserrat</au><au>Martínez-Alcázar, María P.</au><au>Barbas, Coral</au><au>Tempone, Andre G.</au><au>López-Gonzálvez, Ángeles</au><au>Rivas, Luis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><date>2018-11-26</date><risdate>2018</risdate><volume>62</volume><issue>12</issue><issn>0066-4804</issn><eissn>1098-6596</eissn><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.
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.</abstract><cop>1752 N St., N.W., Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>29311090</pmid><pmid>30297370</pmid><doi>10.1128/AAC.01928-18</doi></addata></record> |
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title | Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate |
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