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

Autor:	Schalkwijk J; Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. joost.schalkwijk@radboudumc.nl k.dechering@tropiq.nl., Allman EL; Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802 USA., Jansen PAM; Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., de Vries LE; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Verhoef JMJ; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Jackowski S; St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Botman PNM; Chiralix, Nijmegen, Netherlands., Beuckens-Schortinghuis CA; Chiralix, Nijmegen, Netherlands., Koolen KMJ; TropIQ Health Sciences, Nijmegen, Netherlands., Bolscher JM; TropIQ Health Sciences, Nijmegen, Netherlands., Vos MW; TropIQ Health Sciences, Nijmegen, Netherlands., Miller K; St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Reeves SA; St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Pett H; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Trevitt G; XenoGesis Ltd., Nottingham, UK., Wittlin S; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland., Scheurer C; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland., Sax S; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland., Fischli C; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland., Angulo-Barturen I; The Art of Discovery, Derio, Spain., Jiménez-Diaz MB; The Art of Discovery, Derio, Spain., Josling G; Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802 USA., Kooij TWA; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Bonnert R; Medicines for Malaria Venture, Geneva, Switzerland., Campo B; Medicines for Malaria Venture, Geneva, Switzerland., Blaauw RH; Chiralix, Nijmegen, Netherlands., Rutjes FPJT; Radboud University, Nijmegen, Netherlands., Sauerwein RW; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.; TropIQ Health Sciences, Nijmegen, Netherlands., Llinás M; Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802 USA.; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802 USA., Hermkens PHH; Hermkens Pharma Consultancy, Oss, Netherlands., Dechering KJ; TropIQ Health Sciences, Nijmegen, Netherlands. joost.schalkwijk@radboudumc.nl k.dechering@tropiq.nl.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 Sep 18; Vol. 11 (510).
DOI:	10.1126/scitranslmed.aas9917
Abstrakt:	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. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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