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

18 Sep 2019

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

Science Translational Medicine
PMID: 31534021

Doi: 10.1126/scitranslmed.aas9917

Photo: Jackson_iStock

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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