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-Barturen; Mariá 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

doi:10.1126/scitranslmed.aas9917

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

8 Citations (Scopus)

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 language	English
Article number	eaas9917
Journal	Science Translational Medicine
Volume	11
Issue number	510
DOIs	https://doi.org/10.1126/scitranslmed.aas9917
Publication status	Published - 18 Sep 2019
Externally published	Yes

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Schalkwijk, J., Allman, E. L., Jansen, P. A. M., De Vries, L. E., Verhoef, J. M. J., Jackowski, S., Botman, P. N. M., Beuckens-Schortinghuis, C. A., Koolen, K. M. J., Bolscher, J. M., Vos, M. W., Miller, K., Reeves, S. A., Pett, H., Trevitt, G., Wittlin, S., Scheurer, C., Sax, S., Fischli, C., ... 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.

@article{987a65b980d64d09b29f233812114a63,

title = "Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum",

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.",

author = "Joost Schalkwijk and Allman, {Erik L.} and Jansen, {Patrick A.M.} and {De Vries}, {Laura E.} and Verhoef, {Julie M.J.} and Suzanne Jackowski and Botman, {Peter N.M.} and Beuckens-Schortinghuis, {Christien A.} and Koolen, {Karin M.J.} and Bolscher, {Judith M.} and Vos, {Martijn W.} and Karen Miller and Reeves, {Stacy A.} and Helmi Pett and Graham Trevitt and Sergio Wittlin and Christian Scheurer and Sibylle Sax and Christoph Fischli and I{\~n}igo Angulo-Barturen and Jim{\'e}nez-Diaz, {Mari{\'a} Bel{\'e}n} and Gabrielle Josling and Kooij, {Taco W.A.} and Roger Bonnert and Brice Campo and Blaauw, {Richard H.} and Rutjes, {Floris P.J.T.} and Sauerwein, {Robert W.} and Manuel Llin{\'a}s and Hermkens, {Pedro H.H.} and Dechering, {Koen J.}",

year = "2019",

month = sep,

day = "18",

doi = "10.1126/scitranslmed.aas9917",

language = "English",

volume = "11",

journal = "Science Translational Medicine",

issn = "1946-6234",

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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 journal › Article › Academic › peer-review

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.

U2 - 10.1126/scitranslmed.aas9917

DO - 10.1126/scitranslmed.aas9917

M3 - Article

C2 - 31534021

AN - SCOPUS:85072403566

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 510

M1 - eaas9917

ER -