Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum
- 18 September 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 11 (510)
- https://doi.org/10.1126/scitranslmed.aas9917
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.Keywords
Funding Information
- National Institutes of Health (GM062896)
- National Institutes of Health (AI124507)
- Burroughs Wellcome Fund
- Medicines for Malaria Venture (RD/14/0019)
- Medicines for Malaria Venture (RD/14/0019)
- Medicines for Malaria Venture (RD/14/0019)
- American Lebanese Syrian Associated Charities
- Cancer Center Support (CA21765)
- Netherlands Organization for Scientific Research (NWO-VIDI 864.13.009)
This publication has 54 references indexed in Scilit:
- Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive BacteriaAntimicrobial Agents and Chemotherapy, 2013
- Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen FamiliesPLoS Genetics, 2013
- Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When Serum Pantetheinase Is InactivatedPLOS ONE, 2013
- Metabolomic Analysis via Reversed-Phase Ion-Pairing Liquid Chromatography Coupled to a Stand Alone Orbitrap Mass SpectrometerAnalytical Chemistry, 2010
- Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2RγnullMice Engrafted with Human ErythrocytesAntimicrobial Agents and Chemotherapy, 2009
- The Human Malaria Parasite Plasmodium falciparum Is Not Dependent on Host Coenzyme A BiosynthesisOnline Journal of Public Health Informatics, 2009
- Localization and regulation of mouse pantothenate kinase 2FEBS Letters, 2007
- Feedback Inhibition of Pantothenate Kinase Regulates Pantothenol Uptake by the Malaria ParasiteOnline Journal of Public Health Informatics, 2007
- Clinical Pharmacokinetics and Metabolism of ChloroquineClinical Pharmacokinetics, 1996
- Nutritional Requirements of Plasmodium falciparum in Culture. I. Exogenously Supplied Dialyzable Components Necessary for Continuous GrowthThe Journal of Protozoology, 1985