2. Academic Validation
  3. Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway

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.
Arnau Biosca 1 2 3,  Miriam Ramírez 1,  Alex Gomez-Gomez 4 5,  Aritz Lafuente 1 2 3,  Valentín Iglesias 1 2 3 6,  Oscar J Pozo 4 5,  Santiago Imperial 3 7,  Xavier Fernàndez-Busquets 1 2 3
Affiliations

Affiliations

  • 1 Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, 08036 Barcelona, Spain.
  • 2 Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
  • 3 Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
  • 4 Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, IMIM-Institut Hospital del Mar d'Investigacions Mèdiques, Doctor Aiguader 88, 08003 Barcelona, Spain.
  • 5 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.
  • 6 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
  • 7 Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain.
PMID: 35890216 DOI: 10.3390/pharmaceutics14071320
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.

Keywords

Plasmodium falciparum; antibiotics; antimalarial drugs; domiphen bromide; malaria; methyl erythritol phosphate pathway.

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