Propensity of selecting mutant parasites for the antimalarial drug cabamiquine

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.

Automated summary

This study analyzes the propensity of the antimalarial agent cabamiquine to select for resistant Plasmodium falciparum parasites. Through various studies, resistant mutations at 11 amino acid positions were identified and found to be translatable across models. Mathematical modeling suggests pre-existence of resistant mutants prior to drug exposure, and structural modeling indicates a binding relationship between cabamiquine and mRNA at specific resistance mutations.