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

Science translational medicine (2019-09-20)
Joost Schalkwijk, Erik L Allman, Patrick A M Jansen, Laura E de Vries, Julie M J Verhoef, Suzanne Jackowski, Peter N M Botman, Christien A Beuckens-Schortinghuis, Karin M J Koolen, Judith M Bolscher, Martijn W Vos, Karen Miller, Stacy A Reeves, Helmi Pett, Graham Trevitt, Sergio Wittlin, Christian Scheurer, Sibylle Sax, Christoph Fischli, Iñigo Angulo-Barturen, Mariá Belén Jiménez-Diaz, Gabrielle Josling, Taco W A Kooij, Roger Bonnert, Brice Campo, Richard H Blaauw, Floris P J T Rutjes, Robert W Sauerwein, Manuel Llinás, Pedro H H Hermkens, Koen J Dechering
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Insulin human, recombinant, expressed in yeast (proprietary host)
Supelco
Calcium-d-pantothenate, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Resazurin sodium salt, certified by the Biological Stain Commission
Sigma-Aldrich
Hydrocortisone 21-hemisuccinate sodium salt, powder, BioReagent, suitable for cell culture