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, Ramírez, Miriam, Gómez-Gómez, Àlex, Lafuente, Aritz, Iglesias, Valentin, Pozo Mendoza, Óscar J., 1975-, Imperial, Santiago, Fernàndez Busquets, Xavier
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55137
Acesso em linha:http://hdl.handle.net/10230/55137
http://dx.doi.org/10.3390/pharmaceutics14071320
Access Level:acceso abierto
Palavra-chave:Plasmodium falciparum
Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
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spelling Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathwayBiosca, ArnauRamírez, MiriamGómez-Gómez, ÀlexLafuente, AritzIglesias, ValentinPozo Mendoza, Óscar J., 1975-Imperial, SantiagoFernàndez Busquets, XavierPlasmodium falciparumAntibioticsAntimalarial drugsDomiphen bromideMalariaMethyl erythritol phosphate pathwayThe 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.X.F.-B. was funded by (i) the Spanish Ministry of Science, Innovation and Universities (http://www.ciencia.gob.es/ (accessed on 18 June 2022) and the Spanish State Research Agency (http://www.aei.gob.es/ (accessed on 18 June 2022), grant number RTI2018-094579-B-I00 and by (ii) the Generalitat de Catalunya, Spain (http://agaur.gencat.cat/ (accessed on 18 June 2022), grant number 2017-SGR-908. X.F.-B. and S.I. were funded by the Unión Iberoamericana de Universidades (http://www.uiu.unam.mx (accessed on 18 June 2022), grant number USP-05-2019.MDPI202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/55137http://dx.doi.org/10.3390/pharmaceutics14071320reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésPharmaceutics. 2022 Jun 22;14(7):1320info:eu-repo/grantAgreement/ES/2PE/RTI2018-094579-B-I00© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/551372026-06-12T07:21:37Z
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
Plasmodium falciparum
Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
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
Ramírez, Miriam
Gómez-Gómez, Àlex
Lafuente, Aritz
Iglesias, Valentin
Pozo Mendoza, Óscar J., 1975-
Imperial, Santiago
Fernàndez Busquets, Xavier
author Biosca, Arnau
author_facet Biosca, Arnau
Ramírez, Miriam
Gómez-Gómez, Àlex
Lafuente, Aritz
Iglesias, Valentin
Pozo Mendoza, Óscar J., 1975-
Imperial, Santiago
Fernàndez Busquets, Xavier
author_role author
author2 Ramírez, Miriam
Gómez-Gómez, Àlex
Lafuente, Aritz
Iglesias, Valentin
Pozo Mendoza, Óscar J., 1975-
Imperial, Santiago
Fernàndez Busquets, Xavier
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Plasmodium falciparum
Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
topic Plasmodium falciparum
Antibiotics
Antimalarial drugs
Domiphen bromide
Malaria
Methyl erythritol phosphate pathway
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 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/55137
http://dx.doi.org/10.3390/pharmaceutics14071320
url http://hdl.handle.net/10230/55137
http://dx.doi.org/10.3390/pharmaceutics14071320
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Pharmaceutics. 2022 Jun 22;14(7):1320
info:eu-repo/grantAgreement/ES/2PE/RTI2018-094579-B-I00
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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