Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum

Pantothenamides form antimetabolites that interfere with acetyl-CoA metabolism in the human malaria parasite Plasmodium falciparum. Development of a new antimalarial drug Pantothenenic acid, or vitamin B5, is an essential nutrient for the deadly malaria parasite Plasmodium falciparum. Inhibiting the parasite’s ability to fully metabolize this vitamin using pantothenamide drugs has long been considered a viable antimalarial therapeutic option. Historically, however, pantothenamides have not found success because of an enzyme in human serum that inactivates these molecules. In a new study, Schalkwijk et al. synthesize a series of pantothenamides that contained a modification of the labile bond, rendering them resistant to the action of this enzyme. The authors show that this new class of pantothenamides is converted by the parasite into coenzyme A analogs that are highly potent against malaria parasites at multiple stages of the Plasmodium life cycle. Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum 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 P. falciparum 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 P. falciparum 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.