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dc.contributor.authorMartínez-García, Marta
dc.contributor.authorBart, Jean Mathieu 
dc.contributor.authorCampos-Salinas, Jenny
dc.contributor.authorValdivia, Eva
dc.contributor.authorMartínez-Bueno, Manuel
dc.contributor.authorGonzález-Rey, Elena
dc.contributor.authorNavarro, Miguel
dc.contributor.authorMaqueda, Mercedes
dc.contributor.authorCebrián, Rubén
dc.contributor.authorPérez-Victoria, José M
dc.date.accessioned2020-04-29T07:37:45Z
dc.date.available2020-04-29T07:37:45Z
dc.date.issued2018
dc.identifier.citationInt J Parasitol Drugs Drug Resist. 2018 Aug;8(2):203-212es_ES
dc.identifier.issn2211-3207es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9797
dc.description.abstractThe parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attracted attention as potential parasiticidal compounds. Here, we explore circular bacteriocin AS-48's ability to kill clinically relevant bloodstream forms of T. brucei gambiense, T. brucei rhodesiense and T. brucei brucei. AS-48 exhibited excellent anti-trypanosomal activity in vitro (EC50 = 1-3 nM) against the three T. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. In contrast to its antibacterial action, AS-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. This was evidenced by the fact that vital dye internalization-prohibiting concentrations of AS-48 could kill the parasite at 37 °C but not at 4 °C. Furthermore, AS-48 interacted with the surface of the parasite, at least in part via VSG, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of AS-48. The bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. These changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as AS-48 induced the production of EGFP-ATG8.2-labeled autophagosomes. Collectively, these results indicate AS-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of VSG-bound AS-48 and the induction of autophagic-like cell death. As AS-48 has greater in vitro activity than the drugs currently used to treat T. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana.es_ES
dc.description.sponsorshipWe wish to thank Dr. Michael Duszenko (Interfaculty Institute for Biochemistry, University of Tübingen, Germany), and Prof. Mark Field (University of Dundee, UK) who kindly provided the plasmids pLew100 and p2T7TiCL, respectively. This work was supported by Spanish grants SAF2011-28215 (JMPV), SAF2016-80228-R (JMPV) and SAF2013-48971-C2-1-R (MM) from the Ministerio de Economía y Competitividad, and BIO1786 (JMPV) from the Junta de Andalucía and by FEDER funds from the EU to JMPV. MMG was recipient of a FPI fellowship from the Spanish Ministerio de Economía y Competitividad: SAF2011-28215, SAF2016-80228-R and SAF2013-48971-C2-1-R. MMG was a student of the Biochemistry and Molecular Biology Ph.D. program of the University of Granada (Spain). JMB is funded by “Fondo de Investigación Sanitaria” (FIS) TRPY 1283/15. MN is granted by ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa (RICET) RD12/0018/0015.es_ES
dc.language.isoenges_ES
dc.publisherElsevier es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAS-48es_ES
dc.subjectAntimicrobial peptideses_ES
dc.subjectAutophagyes_ES
dc.subjectSleeping sicknesses_ES
dc.subjectTrypanocidal drugses_ES
dc.subjectTrypanosoma bruceies_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAutophagy es_ES
dc.subject.meshBacteriocins es_ES
dc.subject.meshCell Death es_ES
dc.subject.meshEndocytosis es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMicroscopy, Fluorescence es_ES
dc.subject.meshBody Temperature es_ES
dc.subject.meshTrypanocidal Agents es_ES
dc.subject.meshTrypanosoma brucei brucei es_ES
dc.subject.meshTrypanosoma brucei gambiense es_ES
dc.subject.meshTrypanosoma brucei rhodesiense es_ES
dc.subject.meshTrypanosomiasis, African es_ES
dc.titleAutophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48es_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID29649664es_ES
dc.format.volume8es_ES
dc.format.number2es_ES
dc.format.page203-212es_ES
dc.identifier.doi10.1016/j.ijpddr.2018.03.002es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderRegional Government of Andalusia (España) 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2211-3207es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.ijpddr.2018.03.002es_ES
dc.identifier.journalInternational journal for parasitology. Drugs and drug resistancees_ES
dc.repisalud.centroISCIII::Centro Nacional de Medicina Tropicales_ES
dc.repisalud.institucionISCIIIes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/ BIO1786 (JMPV)es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2011-28215es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2016-80228-Res_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2013-48971-C2-1-Res_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/TRPY 1283/15es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/RD12/0018/0015es_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional