A Novel Antimalarial Agent that Inhibits Protein Synthesis in <i>Plasmodium falciparum</i>

The emergence of drug resistance to nearly all antimalarials following their rollout underscores the need for novel chemotypes with novel modes 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 2-hydroxyphenyl benzamide scaffold, displays potent activity against blood-stage and mature sexual stages of Plasmodium falciparum and no toxicity in human cells. Resistance selection studies with 31 identified a previously unknown point mutation in the P. falciparum multidrug-resistance protein 1 (pfmdr1) gene, for which we confirmed causality by CRISPR/Cas9-based gene editing as the primary mediator of resistance. No cross-resistance toward first-line antimalarials was identified in compound 31-resistant parasites. 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.