Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway

The evolution of resistance by the malaria parasite to artemisinin, the key component of the combination therapy strategies that are at the core of current antimalarial treatments, calls for the urgent identification of new fast-acting antimalarials. The apicoplast organelle is a preferred target of...

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Autores: Biosca, Arnau|||0000-0002-3047-8991, Ramírez Moreno, Miriam|||0000-0002-9823-319X, Gomez-Gomez, A.|||0000-0001-8172-1827, Lafuente, Aritz|||0000-0002-1497-5744, Iglesias, Valentin|||0000-0002-6133-0869, Pozo, Oscar J.|||0000-0002-1735-9728, Imperial, Santiago|||0000-0001-8749-1428, Fernández Busquets, Xavier|||0000-0002-4622-9631
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:292525
Acceso en línea:https://ddd.uab.cat/record/292525
https://dx.doi.org/urn:doi:10.3390/pharmaceutics14071320
Access Level:acceso abierto
Palabra clave:Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
Plasmodium falciparum
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spelling Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate PathwayBiosca, Arnau|||0000-0002-3047-8991Ramírez Moreno, Miriam|||0000-0002-9823-319XGomez-Gomez, A.|||0000-0001-8172-1827Lafuente, Aritz|||0000-0002-1497-5744Iglesias, Valentin|||0000-0002-6133-0869Pozo, Oscar J.|||0000-0002-1735-9728Imperial, Santiago|||0000-0001-8749-1428Fernández Busquets, Xavier|||0000-0002-4622-9631AntibioticsAntimalarial drugsDomiphen bromideMalariaMethyl erythritol phosphate pathwayPlasmodium falciparumThe evolution of resistance by the malaria parasite to artemisinin, the key component of the combination therapy strategies that are at the core of current antimalarial treatments, calls for the urgent identification of new fast-acting antimalarials. The apicoplast organelle is a preferred target of antimalarial drugs because it contains biochemical processes absent from the human host. Fosmidomycin is the only drug in clinical trials targeting the apicoplast, where it inhibits the methyl erythritol phosphate (MEP) pathway. Here, we characterized the antiplasmodial activity of domiphen bromide (DB), another MEP pathway inhibitor with a rapid mode of action that arrests the in vitro growth of Plasmodium falciparum at the early trophozoite stage. Metabolomic analysis of the MEP pathway and Krebs cycle intermediates in 20 µM DB-treated parasites suggested a rapid activation of glycolysis with a concomitant decrease in mitochondrial activity, consistent with a rapid killing of the pathogen. These results present DB as a model compound for the development of new, potentially interesting drugs for future antimalarial combination therapies.Universitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/292525https://dx.doi.org/urn:doi:10.3390/pharmaceutics14071320reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-094579-B-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2925252026-06-06T12:50:31Z
dc.title.none.fl_str_mv Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
title Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
spellingShingle Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
Biosca, Arnau|||0000-0002-3047-8991
Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
Plasmodium falciparum
title_short Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
title_full Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
title_fullStr Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
title_full_unstemmed Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
title_sort Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway
dc.creator.none.fl_str_mv Biosca, Arnau|||0000-0002-3047-8991
Ramírez Moreno, Miriam|||0000-0002-9823-319X
Gomez-Gomez, A.|||0000-0001-8172-1827
Lafuente, Aritz|||0000-0002-1497-5744
Iglesias, Valentin|||0000-0002-6133-0869
Pozo, Oscar J.|||0000-0002-1735-9728
Imperial, Santiago|||0000-0001-8749-1428
Fernández Busquets, Xavier|||0000-0002-4622-9631
author Biosca, Arnau|||0000-0002-3047-8991
author_facet Biosca, Arnau|||0000-0002-3047-8991
Ramírez Moreno, Miriam|||0000-0002-9823-319X
Gomez-Gomez, A.|||0000-0001-8172-1827
Lafuente, Aritz|||0000-0002-1497-5744
Iglesias, Valentin|||0000-0002-6133-0869
Pozo, Oscar J.|||0000-0002-1735-9728
Imperial, Santiago|||0000-0001-8749-1428
Fernández Busquets, Xavier|||0000-0002-4622-9631
author_role author
author2 Ramírez Moreno, Miriam|||0000-0002-9823-319X
Gomez-Gomez, A.|||0000-0001-8172-1827
Lafuente, Aritz|||0000-0002-1497-5744
Iglesias, Valentin|||0000-0002-6133-0869
Pozo, Oscar J.|||0000-0002-1735-9728
Imperial, Santiago|||0000-0001-8749-1428
Fernández Busquets, Xavier|||0000-0002-4622-9631
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
Plasmodium falciparum
topic Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
Plasmodium falciparum
description The evolution of resistance by the malaria parasite to artemisinin, the key component of the combination therapy strategies that are at the core of current antimalarial treatments, calls for the urgent identification of new fast-acting antimalarials. The apicoplast organelle is a preferred target of antimalarial drugs because it contains biochemical processes absent from the human host. Fosmidomycin is the only drug in clinical trials targeting the apicoplast, where it inhibits the methyl erythritol phosphate (MEP) pathway. Here, we characterized the antiplasmodial activity of domiphen bromide (DB), another MEP pathway inhibitor with a rapid mode of action that arrests the in vitro growth of Plasmodium falciparum at the early trophozoite stage. Metabolomic analysis of the MEP pathway and Krebs cycle intermediates in 20 µM DB-treated parasites suggested a rapid activation of glycolysis with a concomitant decrease in mitochondrial activity, consistent with a rapid killing of the pathogen. These results present DB as a model compound for the development of new, potentially interesting drugs for future antimalarial combination therapies.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/292525
https://dx.doi.org/urn:doi:10.3390/pharmaceutics14071320
url https://ddd.uab.cat/record/292525
https://dx.doi.org/urn:doi:10.3390/pharmaceutics14071320
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-094579-B-I00
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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