Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum
Science Translational Medicine • 18 Sep 2019 • Vol 11, Issue 510 • DOI: 10.1126/scitranslmed.aas9917
Development of a new antimalarial drug
Pantothenenic acid, or vitamin B5, is an essential nutrient for the deadly malaria parasite Plasmodium falciparum. Inhibiting the parasite’s ability to fully metabolize this vitamin using pantothenamide drugs has long been considered a viable antimalarial therapeutic option. Historically, however, pantothenamides have not found success because of an enzyme in human serum that inactivates these molecules. In a new study, Schalkwijk et al. synthesize a series of pantothenamides that contained a modification of the labile bond, rendering them resistant to the action of this enzyme. The authors show that this new class of pantothenamides is converted by the parasite into coenzyme A analogs that are highly potent against malaria parasites at multiple stages of the Plasmodium life cycle.
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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Supplementary Material
Summary
Materials and Methods
Fig. S1. Pantothenamide stability.
Fig. S2. Parasite life cycle.
Fig. S3. Pantothenate competition assays.
Fig. S4. PANK activity.
Fig. S5. Expression of PfPANK1.
Fig. S6. Cellular pantothenamide metabolism and targeted metabolomics.
Fig. S7. Pantothenate and pantothenamide metabolism in saponin-isolated parasites versus uninfected red blood cells.
Fig. S8. Erythrocytes preexposed to MMV689258 are less susceptible to malaria infection.
Fig. S9. Drug-resistant parasite (ACS-T627A and ACS11-E660K) transmission to mosquitoes.
Fig. S10. Pantothenamide-resistant parasites (ACS-T627A and ACS11-E660K) have reduced fitness.
Fig. S11. Sequence verification of CRISPR-Cas9–engineered mutations.
Fig. S12. Metabolomics of wild-type versus drug-resistant parasites.
Fig. S13. Pharmacokinetics of MMV689258 in rodents.
Fig. S14. Dose-normalized plasma exposure of MMV689258 in NODscidIL2Rγnull mice.
Fig. S15. Red blood cell counts in PfSCID mice treated with MMV689258.
Fig. S16. Cell-type specificity and primary human hepatocyte metabolomics.
Table S1. Selection of compounds to illustrate structure-activity relationship.
Table S2. IC50 values of compounds shown in Fig. 1.
Table S3. Description of strains used in resistance panel.
Table S4. Targeted metabolomics values for select compounds of interest.
Table S5. Pharmacokinetic parameters derived from the data shown in fig. S13.
Table S6. Renal excretion of MMV689258 in rats.
Table S7. Biliary excretion of MMV689258 in rats.
Table S8. In vitro ADME parameters of MMV689258.
Table S9. Primers used for genetic studies.
Resources
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Science Translational Medicine
Volume 11 | Issue 510
September 2019
September 2019
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 12 January 2018
Accepted: 28 March 2019
Acknowledgments
We thank J. Burrows for advice and discussion and the Lygature product development partnership for help with project management. A cDNA encoding PfPANK1 was provided to S.J. by C. Ben Mamoun. M. Lee is acknowledged for contributing a pDC2-based gene targeting vector. We also thank the Huck Institutes of Life Sciences core facilities, Genomics Core Facility, and Metabolomics Core Facility at Penn State University. A. Patterson and P. Smith from the Penn State Metabolomics Core are acknowledged for technical and metabolomics expertise. We thank S. Charman and K. White from the Center for Drug Candidate Optimisation of Monash University for in vitro DMPK assays. We thank T. Mal, director of the Penn State University NMR facility, for assistance using the Bruker AVIII-HD-500 NMR and for help with spectral annotations. Funding: This work was supported by National Institutes of Health grant no. GM062896 (S.J.), Cancer Center Support grant no. CA21765 (S.J.), Medicines for Malaria Venture grant no. RD/14/0019 (K.J.D., M.L., and J.S.), Burroughs Wellcome Fund Investigators in Pathogenesis of Infectious Disease (PATH) Award (M.L.), NIH Ruth Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (F32) AI124507 (E.L.A.), and the American Lebanese Syrian Associated Charities (S.J.). T.W.A.K. was supported by the Netherlands Organization for Scientific Research (no. NWO-VIDI 864.13.009). The Illumina HiSeq 2500 (Penn State University) was purchased with NSF-MRI award no. DBI-1229046. The AB Sciex TripleTOF 5600 was purchased with NSF-MRI award no. CBET-1126373. Author contributions: J.S., P.H.H.H., and K.J.D. conceived the work and did overall supervision and analysis of parasitology, medicinal chemistry, biochemistry, and molecular biology. E.L.A. performed and analyzed metabolomics and whole genome sequencing data. P.A.M.J. performed and analyzed molecular biology and biochemistry assays. L.E.d.V., J.M.J.V., G.J., and M.W.V. performed molecular biology and generation of parasite mutants. M.L. designed, supervised, and analyzed metabolomics and whole genome sequencing data. S.J., K.M., and S.A.R. generated recombinant enzymes. P.N.M.B. and C.A.B.-S. performed organic chemistry experiments. H.P., K.M.J.K., J.M.B., and M.W.V. performed in vitro parasitology assays. T.W.A.K. and R.W.S. supervised parasite mutant generation and in vitro parasitology experiments. R.H.B., F.P.J.T.R., and R.B. supervised organic chemistry experiments. G.T. designed and analyzed DMPK experiments. S.W., C.S., S.S., C.F., M.B.J.-D., and I.A.-B. performed efficacy and pharmacokinetics studies in SCID mice. B.C. advised on parasitology and drug development. J.S., E.L.A., P.A.M.J., L.E.d.V., M.L., and K.J.D. wrote the manuscript. All authors proofread and edited the manuscript. Competing interests: K.J.D. and R.W.S. hold stock in TropIQ Health Sciences B.V. Part of this work is described in patent application no. PCT/NL2015/050774, entitled “Pantothenamide Analogues” (coinventors P.H.H.H., P.A.M.J., J.S., and P.N.M.B.). E.L.A. is currently employed by Janssen Pharmaceuticals Inc. P.N.M.B. is currently employed by Aspen Healthcare. F.P.J.T.R. is a consultant of Enzyme Inc. and FutureChemistry Inc. S.J. is a member of the advisory board of CoA Therapeutics Inc. R.B. is a consultant for MMV and Potter Clarkson Inc. P.H.H.H. is a consultant for TropIQ Health Sciences B.V. Data and materials availability: All data associated with this study are present in the paper and/or the Supplementary Materials. Raw NMR spectra and metabolomics data have been deposited in the NIH metabolomics workbench repository. The project ID is PR000829, studies ST001239 and ST001238. Whole genome sequencing data (FastQ) of the lab-generated resistant parasite lines has been deposited in the NIH Sequence Read Archive (SRA) BioProject ID no. PRJNA560380. The genetically engineered P. falciparum parasite lines described here are available from T.W.A.K. under a material transfer agreement (MTA) with the Radboud University Medical Center. The pantothenamide compounds can be made available to researchers through an MTA by submitting a request to K.J.D.
Authors
Funding Information
National Institutes of Health: GM062896
National Institutes of Health: AI124507
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
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