Propensity of selecting mutant parasites for the antimalarial drug cabamiquine

Eva Stadler, Mohamed Maiga, Lukas Friedrich, Vandana Thathy, Claudia Demarta-Gatsi, Antoine Dara, Fanta Sogore, Josefine Striepen, Claude Oeuvray, Abdoulaye A. Djimdé, Marcus C. S. Lee, Laurent Dembélé (), David A. Fidock (), David S. Khoury () and Thomas Spangenberg ()
Additional contact information
Eva Stadler: UNSW Sydney
Mohamed Maiga: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Faculté de Pharmacie, Malaria Research and Training Center (MRTC), Point G
Lukas Friedrich: Medicinal Chemistry & Drug Design Global Research & Development, Discovery Technologies, Merck Healthcare
Vandana Thathy: Columbia University Irving Medical Center
Claudia Demarta-Gatsi: Global Health Institute of Merck
Antoine Dara: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Faculté de Pharmacie, Malaria Research and Training Center (MRTC), Point G
Fanta Sogore: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Faculté de Pharmacie, Malaria Research and Training Center (MRTC), Point G
Josefine Striepen: Columbia University Irving Medical Center
Claude Oeuvray: Global Health Institute of Merck
Abdoulaye A. Djimdé: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Faculté de Pharmacie, Malaria Research and Training Center (MRTC), Point G
Marcus C. S. Lee: Wellcome Sanger Institute, Wellcome Genome Campus
Laurent Dembélé: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Faculté de Pharmacie, Malaria Research and Training Center (MRTC), Point G
David A. Fidock: Columbia University Irving Medical Center
David S. Khoury: UNSW Sydney
Thomas Spangenberg: Global Health Institute of Merck

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract We report an analysis of the propensity of the antimalarial agent cabamiquine, a Plasmodium-specific eukaryotic elongation factor 2 inhibitor, to select for resistant Plasmodium falciparum parasites. Through in vitro studies of laboratory strains and clinical isolates, a humanized mouse model, and volunteer infection studies, we identified resistance-associated mutations at 11 amino acid positions. Of these, six (55%) were present in more than one infection model, indicating translatability across models. Mathematical modelling suggested that resistant mutants were likely pre-existent at the time of drug exposure across studies. Here, we estimated a wide range of frequencies of resistant mutants across the different infection models, much of which can be attributed to stochastic differences resulting from experimental design choices. Structural modelling implicates binding of cabamiquine to a shallow mRNA binding site adjacent to two of the most frequently identified resistance mutations.

Date: 2023
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DOI: 10.1038/s41467-023-40974-8

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