2. Academic Validation
  3. Expanding the Chemical Space of Reverse Fosmidomycin Analogs

Expanding the Chemical Space of Reverse Fosmidomycin Analogs

  • ACS Med Chem Lett. 2024 Dec 23;16(1):136-143. doi: 10.1021/acsmedchemlett.4c00501.
Talea Knak 1,  Sana Takada 2,  Boris Illarionov 3,  Violetta Krisilia 4,  Lais Pessanha de Carvalho 5,  Beate Lungerich 1,  Yasumitsu Sakamoto 6,  Stefan Höfmann 1,  Adelbert Bacher 3 7,  Rainer Kalscheuer 4,  Jana Held 5 8,  Markus Fischer 3,  Nobutada Tanaka 2,  Thomas Kurz 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 2 School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan.
  • 3 Hamburg School of Food Science, Universität Hamburg, Grindelallee 117, 20146 Hamburg, Germany.
  • 4 Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 5 Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Wilhelmstr. 27, 72074 Tübingen, Germany.
  • 6 School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
  • 7 TUM School of Natural Sciences, Technical University of Munich, Boltzmannstr. 10, 85748 Garching, Germany.
  • 8 German Center for Infection Research (DZIF), partner site Tübingen, 72074 Tübingen, Germany.
PMID: 39811140 DOI: 10.1021/acsmedchemlett.4c00501
Abstract

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 Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis 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 in vitro growth inhibition of the pathogens. Crystallographic studies revealed that compounds 12a and 12b induce an open PfDXR conformation and that the Enzyme selectively binds the S-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.

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