A novel antimalarial agent that inhibits protein synthesis in Plasmodium falciparum

ABSTRACT: Drug resistance to nearly all antimalarials following their rollout underscores the need for novel chemotypes with novel mode of action to replenish the antimalarial drug-development pipeline. We identified a novel class of compounds in the antimalarial armory. Compound 31, characterized by a hydroxybenzamide scaffold, displays potent activity against blood-stage and late sexual stages of Plasmodium falciparum and no toxicity in human cells. Resistance selection studies with 31 identified a novel point mutation in the P. falciparum multidrug-resistance protein 1 (pfmdr1) gene, which was confirmed by CRISPR/Cas9-based gene editing as the primary mediator of resistance. Despite this, no cross-resistance towards first-line antimalarials were identified. Proteomics studies indicated that the primary mode of action of 31 is through direct binding to cytosolic ribosomal subunits, thereby inhibiting protein synthesis in the parasite. Taken together, compound 31 is a promising starting point for the development of a next-generation antimalarial.

INSTRUMENT(S):

ORGANISM(S): Plasmodium Falciparum Nf54

SUBMITTER: Lorenzo Bizzarri  

LAB HEAD: Anna Hirsch

PROVIDER: PXD065399 | Pride | 2025-12-08

REPOSITORIES: Pride