Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathway
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Biosca, Arnau
- dc.contributor.author Ramírez, Miriam
- dc.contributor.author Gomez-Gomez, Àlex
- dc.contributor.author Lafuente, Aritz
- dc.contributor.author Iglesias, Valentin
- dc.contributor.author Pozo Mendoza, Óscar J., 1975-
- dc.contributor.author Imperial, Santiago
- dc.contributor.author Fernàndez Busquets, Xavier
- dc.date.accessioned 2022-12-14T07:41:41Z
- dc.date.available 2022-12-14T07:41:41Z
- dc.date.issued 2022
- dc.description.abstract 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.
- dc.description.sponsorship 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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Biosca A, Ramírez M, Gomez-Gomez A, Lafuente A, Iglesias V, Pozo OJ, Imperial S, Fernàndez-Busquets X. Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathway. Pharmaceutics. 2022 Jun 22;14(7):1320. DOI: 10.3390/pharmaceutics14071320
- dc.identifier.doi http://dx.doi.org/10.3390/pharmaceutics14071320
- dc.identifier.issn 1999-4923
- dc.identifier.uri http://hdl.handle.net/10230/55137
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.ispartof Pharmaceutics. 2022 Jun 22;14(7):1320
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094579-B-I00
- dc.rights © 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/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Plasmodium falciparum
- dc.subject.keyword Antibiotics
- dc.subject.keyword Antimalarial drugs
- dc.subject.keyword Domiphen bromide
- dc.subject.keyword Malaria
- dc.subject.keyword Methyl erythritol phosphate pathway
- dc.title Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathway
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion