Propensity of selecting mutant parasites for the antimalarial drug cabamiquine

TY - JOUR

T1 - Propensity of selecting mutant parasites for the antimalarial drug cabamiquine

AU - Stadler, Eva

AU - Maiga, Mohamed

AU - Friedrich, Lukas

AU - Thathy, Vandana

AU - Demarta-Gatsi, Claudia

AU - Dara, Antoine

AU - Sogore, Fanta

AU - Striepen, Josefine

AU - Oeuvray, Claude

AU - Djimdé, Abdoulaye A.

AU - Lee, Marcus C. S.

AU - Dembélé, Laurent

AU - Fidock, David A.

AU - Khoury, David S.

AU - Spangenberg, Thomas

N1 - Funding Information: Partial funding from Merck KGaA, Darmstadt, Germany is gratefully acknowledged. D.A.F. acknowledges partial funding from Medicines for Malaria Venture (RD-08-0015), the Bill & Melinda Gates Foundation (INV —033538), and Merck KGaA, Darmstadt, Germany. Copyright: © 2023. Springer Nature Limited.

PY - 2023/8/25

Y1 - 2023/8/25

N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Antimalarials/pharmacology

KW - Parasites

KW - Amino Acids

KW - Binding Sites

KW - Disease Models, Animal

UR - https://www.scopus.com/pages/publications/85168718243

U2 - 10.1038/s41467-023-40974-8

DO - 10.1038/s41467-023-40974-8

M3 - Article

C2 - 37626093

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 5205

ER -