| Literature DB >> 31534021 |
Joost Schalkwijk1, Erik L Allman2, Patrick A M Jansen3, Laura E de Vries4, Julie M J Verhoef4, Suzanne Jackowski5, Peter N M Botman6, Christien A Beuckens-Schortinghuis6, Karin M J Koolen7, Judith M Bolscher7, Martijn W Vos7, Karen Miller5, Stacy A Reeves5, Helmi Pett4, Graham Trevitt8, Sergio Wittlin9,10, Christian Scheurer9,10, Sibylle Sax9,10, Christoph Fischli9,10, Iñigo Angulo-Barturen11, Mariá Belén Jiménez-Diaz11, Gabrielle Josling2, Taco W A Kooij4, Roger Bonnert12, Brice Campo12, Richard H Blaauw6, Floris P J T Rutjes13, Robert W Sauerwein4,7, Manuel Llinás2,14, Pedro H H Hermkens15, Koen J Dechering16.
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.Entities:
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Year: 2019 PMID： 31534021 DOI： 10.1126/scitranslmed.aas9917
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956