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

Joost Schalkwijk, Erik L. Allman, Patrick A.M. Jansen, Laura E. De Vries, Julie M.J. Verhoef, Suzanne Jackowski, Peter N.M. Botman, Christien A. Beuckens-Schortinghuis, Karin M.J. Koolen, Judith M. Bolscher, Martijn W. Vos, Karen Miller, Stacy A. Reeves, Helmi Pett, Graham Trevitt, Sergio Wittlin, Christian Scheurer, Sibylle Sax, Christoph Fischli, Iñigo Angulo-BarturenMariá Belén Jiménez-Diaz, Gabrielle Josling, Taco W.A. Kooij, Roger Bonnert, Brice Campo, Richard H. Blaauw, Floris P.J.T. Rutjes, Robert W. Sauerwein, Manuel Llinás, Pedro H.H. Hermkens, Koen J. Dechering

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbereaas9917
JournalScience Translational Medicine
Volume11
Issue number510
DOIs
StatePublished - Sep 18 2019

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Acetyl Coenzyme A
Antimalarials
Plasmodium falciparum
Parasites
Malaria
Coenzyme A
Acetate-CoA Ligase
Clustered Regularly Interspaced Short Palindromic Repeats
Coenzyme A Ligases
Mutation
Metabolomics
Plasmodium
Enzymes
Pharmacokinetics
Serum
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Schalkwijk, J., Allman, E. L., Jansen, P. A. M., De Vries, L. E., Verhoef, J. M. J., Jackowski, S., ... Dechering, K. J. (2019). Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Science Translational Medicine, 11(510), [eaas9917]. https://doi.org/10.1126/scitranslmed.aas9917
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. In: Science Translational Medicine. 2019 ; Vol. 11, No. 510.
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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.",
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Schalkwijk, J, Allman, EL, Jansen, PAM, De Vries, LE, Verhoef, JMJ, Jackowski, S, Botman, PNM, Beuckens-Schortinghuis, CA, Koolen, KMJ, Bolscher, JM, Vos, MW, Miller, K, Reeves, SA, Pett, H, Trevitt, G, Wittlin, S, Scheurer, C, Sax, S, Fischli, C, Angulo-Barturen, I, Jiménez-Diaz, MB, Josling, G, Kooij, TWA, Bonnert, R, Campo, B, Blaauw, RH, Rutjes, FPJT, Sauerwein, RW, Llinás, M, Hermkens, PHH & Dechering, KJ 2019, 'Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum', Science Translational Medicine, vol. 11, no. 510, eaas9917. https://doi.org/10.1126/scitranslmed.aas9917

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

In: Science Translational Medicine, Vol. 11, No. 510, eaas9917, 18.09.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum

AU - Schalkwijk, Joost

AU - Allman, Erik L.

AU - Jansen, Patrick A.M.

AU - De Vries, Laura E.

AU - Verhoef, Julie M.J.

AU - Jackowski, Suzanne

AU - Botman, Peter N.M.

AU - Beuckens-Schortinghuis, Christien A.

AU - Koolen, Karin M.J.

AU - Bolscher, Judith M.

AU - Vos, Martijn W.

AU - Miller, Karen

AU - Reeves, Stacy A.

AU - Pett, Helmi

AU - Trevitt, Graham

AU - Wittlin, Sergio

AU - Scheurer, Christian

AU - Sax, Sibylle

AU - Fischli, Christoph

AU - Angulo-Barturen, Iñigo

AU - Jiménez-Diaz, Mariá Belén

AU - Josling, Gabrielle

AU - Kooij, Taco W.A.

AU - Bonnert, Roger

AU - Campo, Brice

AU - Blaauw, Richard H.

AU - Rutjes, Floris P.J.T.

AU - Sauerwein, Robert W.

AU - Llinás, Manuel

AU - Hermkens, Pedro H.H.

AU - Dechering, Koen J.

PY - 2019/9/18

Y1 - 2019/9/18

N2 - 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.

AB - 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.

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U2 - 10.1126/scitranslmed.aas9917

DO - 10.1126/scitranslmed.aas9917

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JO - Science Translational Medicine

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