Targeting <i>Plasmodium falciparum</i> IspD in the Methyl- <scp>d</scp> -erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity
The methyl-d-erythritol phosphate (MEP) pathway has emerged as an interesting target in the fight against antimicrobial resistance. The pathway is essential in many human pathogens, including <i>Plasmodium falciparum</i> (<i>Pf</i>), but is absent in human cells. In the present study, we report on the discovery of a new chemical class targeting IspD, the third enzyme in the pathway. Exploration of the structure-activity relationship yielded inhibitors with potency in the low-nanomolar range. Moreover, we investigated the whole-cell activity, mode of inhibition, metabolic, and plasma stability of this compound class, and conducted <i>in vivo</i> pharmacokinetic profiling on selected compounds. Lastly, we disclosed a new mass spectrometry (MS)-based enzymatic assay for direct IspD activity determination, circumventing the need for auxiliary enzymes. In summary, we have identified a readily synthesizable compound class, demonstrating excellent activity and a promising profile, positioning it as a valuable tool compound for advancing research on IspD.
Authors
- Deepika Kannan (ORCID: https://orcid.org/0000-0002-1267-6193)
- Markus Fischer (ORCID: https://orcid.org/0000-0001-7243-4199)
- Mostafa M. Hamed (ORCID: https://orcid.org/0000-0002-7374-6992)
- Audrey R. Odom John (ORCID: https://orcid.org/0000-0001-8395-8537)
- Hannes Hahne (ORCID: https://orcid.org/0000-0003-3601-0051)
- Daan Willocx (ORCID: https://orcid.org/0000-0001-6990-8349)
- Alaa Alhayek (ORCID: https://orcid.org/0000-0001-8192-6574)
- Matthias Rottmann (ORCID: https://orcid.org/0000-0002-2207-7899)
- Eleonora Diamanti (ORCID: https://orcid.org/0000-0001-8392-5575)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Andreas M. Kany (ORCID: https://orcid.org/0000-0001-7580-3658)
- Matthias Witschel (ORCID: https://orcid.org/0000-0003-0537-5146)
- Patricia Bravo (ORCID: https://orcid.org/0000-0001-5454-3826)
- Boris Illarionov (ORCID: https://orcid.org/0009-0007-8489-0651)
- Jonas Lohse (ORCID: https://orcid.org/0000-0002-5904-2390)
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
- Lorenzo Bizzarri (ORCID: https://orcid.org/0009-0003-7017-5770)
Institutions
- Children's Hospital of Philadelphia (US)
- Swiss Tropical and Public Health Institute (CH)
- Universität Hamburg (DE)
- University of Basel (CH)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE)
- University of Pennsylvania (US)
- Robert Bosch (Germany) (DE)
- Saarland University (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c00212
- Citations
- 6
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Universität Basel
- Deutsches Zentrum für Infektionsforschung
- European Commission
- Universität des Saarlandes
- Universität Hamburg
- Università di Bologna
- Perelman School of Medicine, University of Pennsylvania
- H2020 Marie Skłodowska-Curie Actions