Expanding the Chemical Space of Reverse Fosmidomycin Analogs
Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for <i>Plasmodium falciparum</i>, <i>Escherichia coli</i>, and <i>Mycobacterium tuberculosis</i> that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no <i>in vitro</i> growth inhibition of the pathogens. Crystallographic studies revealed that compounds <b>12a</b> and <b>12b</b> induce an open <i>Pf</i>DXR conformation and that the enzyme selectively binds the <i>S</i>-enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies.
Authors
- Jana Held (ORCID: https://orcid.org/0000-0002-7970-1429)
- Thomas Kurz (ORCID: https://orcid.org/0000-0002-9474-4224)
- Markus Fischer (ORCID: https://orcid.org/0000-0001-7243-4199)
- Beate Lungerich
- Talea Knak (ORCID: https://orcid.org/0000-0002-9185-5156)
- Stefan Höfmann (ORCID: https://orcid.org/0000-0003-0588-6974)
- Rainer Kalscheuer (ORCID: https://orcid.org/0000-0002-3378-2067)
- Boris Illarionov (ORCID: https://orcid.org/0009-0007-8489-0651)
- Adelbert Bacher (ORCID: https://orcid.org/0000-0001-5174-4139)
- Laís Pessanha de Carvalho (ORCID: https://orcid.org/0000-0002-3857-5462)
- Violetta Krisilia (ORCID: https://orcid.org/0009-0000-3256-8627)
- Nobutada Tanaka (ORCID: https://orcid.org/0000-0001-5365-4698)
- Sana Takada (ORCID: https://orcid.org/0009-0006-7357-244X)
- Yasumitsu Sakamoto (ORCID: https://orcid.org/0000-0003-1067-954X)
Institutions
- Universität Hamburg (DE)
- Iwate Medical University (JP)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- German Center for Infection Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- Kitasato University (JP)
- University of Tübingen (DE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00501
- Citations
- 1
- Primary Topic
- Plant biochemistry and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Japan Society for the Promotion of Science London
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Heiwa Nakajima Foundation