Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathway

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.

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.