2. Academic Validation
  3. Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR)

Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR)

  • ACS Infect Dis. 2024 May 10;10(5):1739-1752. doi: 10.1021/acsinfecdis.4c00100.
Mona A Abdullaziz 1 2,  Sana Takada 3,  Boris Illarionov 4,  Lais Pessanha de Carvalho 5,  Yasumitsu Sakamoto 6,  Stefan Höfmann 1,  Talea Knak 1,  Anna-Lene Kiffe-Delf 7,  Flaminia Mazzone 8,  Klaus Pfeffer 8,  Rainer Kalscheuer 7,  Adelbert Bacher 4 9,  Jana Held 5 10,  Markus Fischer 4,  Nobutada Tanaka 3,  Thomas Kurz 1
Affiliations

Affiliations

  • 1 Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 2 National Research Centre (NRC), 33 El Buhouth St, Ad Doqi, Dokki, Cairo 12622, Egypt.
  • 3 School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan.
  • 4 Hamburg School of Food Science, Universität Hamburg, Grindelallee 117, 20146 Hamburg, 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 Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 8 Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University, University Hospital Düsseldorf, Germany, 40225 Düsseldorf, Germany.
  • 9 TUM School of Natural Sciences, Technical University of Munich, Boltzmannstr. 10, 85748 Garching, Germany.
  • 10 German Center for Infection Research (DZIF), partner site Tübingen, 72074 Tübingen, Germany.
PMID: 38647213 DOI: 10.1021/acsinfecdis.4c00100
Abstract

Reverse analogs of the phosphonohydroxamic acid Antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis Enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar PfDXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good Parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, PfDXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker.

Keywords

1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC); N-substituted hydroxamic acids; antiplasmodial activity; cocrystal structures; fosmidomycin; nonmevalonate biosynthesis pathway.

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