Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in <i>Plasmodium falciparum</i>

Abstract

Malaria eradication is critically dependent on new therapeutics that target resistant <i>Plasmodium</i> parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage <i>Plasmodium falciparum</i> parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of <i>P. falciparum</i> infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl-coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl-coenzyme A synthetase and acyl-coenzyme A synthetase 11. Introduction and reversion of these mutations in <i>P. falciparum</i> using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites.