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Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4514042
Author(s)
Schalkwijk, Joost; Allman, Erik L.; Jansen, Patrick A. M.; de Vries, Laura E.; Verhoef, Julie M. J.; Jackowski, Suzanne; Botman, Peter N. M.; Beuckens-Schortinghuis, Christien A.; Koolen, Karin M. J.; Bolscher, Judith M.; Vos, Martijn W.; Miller, Karen; Reeves, Stacy A.; Pett, Helmi; Trevitt, Graham; Wittlin, Sergio; Scheurer, Christian; Sax, Sibylle; Fischli, Christoph; Angulo-Barturen, Iñigo; Jiménez-Diaz, Mariá Belén; Josling, Gabrielle; Kooij, Taco W. A.; Bonnert, Roger; Campo, Brice; Blaauw, Richard H.; Rutjes, Floris P. J. T.; Sauerwein, Robert W.; Llinás, Manuel; Hermkens, Pedro H. H.; Dechering, Koen J.
Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum
Journal
Science Translational Medicine
Volume
11
Number
510
Pages / Article-Number
eaas9917
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.
Publisher
American Association for the Advancement of Science
