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

Schalkwijk, Joost and Allman, Erik L. and Jansen, Patrick A. M. and de Vries, Laura E. and Verhoef, Julie M. J. and Jackowski, Suzanne and Botman, Peter N. M. and Beuckens-Schortinghuis, Christien A. and Koolen, Karin M. J. and Bolscher, Judith M. and Vos, Martijn W. and Miller, Karen and Reeves, Stacy A. and Pett, Helmi and Trevitt, Graham and Wittlin, Sergio and Scheurer, Christian and Sax, Sibylle and Fischli, Christoph and Angulo-Barturen, Iñigo and Jiménez-Diaz, Mariá Belén and Josling, Gabrielle and Kooij, Taco W. A. and Bonnert, Roger and Campo, Brice and Blaauw, Richard H. and Rutjes, Floris P. J. T. and Sauerwein, Robert W. and Llinás, Manuel and Hermkens, Pedro H. H. and Dechering, Koen J.. (2019) Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Science Translational Medicine, 11 (510). eaas9917.

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Official URL: https://edoc.unibas.ch/72027/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio and Scheurer, Christian and Sax, Sibylle and Fischli, Christoph
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
e-ISSN:1946-6242
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:30 Sep 2019 07:38
Deposited On:30 Sep 2019 07:38

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