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

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

Schalkwijk J, Allman EL, Jansen PAM, de Vries LE, Verhoef JMJ, Jackowski S, Botman PNM, Beuckens-Schortinghuis CA, Koolen KMJ, Bolscher JM, Vos MW, Miller K, Reeves SA, Pett H, Trevitt G, Wittlin S, Scheurer C, Sax S, Fischli C, Angulo-Barturen I, Jiménez-Diaz MB, Josling G, Kooij TWA, Bonnert R, Campo B, Blaauw RH, Rutjes FPJT, Sauerwein RW, Llinás M, Hermkens PHH, Dechering KJ

Malaria eradication is critically dependent on new therapeutics that target resistant parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage 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 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 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.

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