2. Academic Validation
  3. Identification and Biochemical Characterization of Pyrrolidinediones as Novel Inhibitors of the Bacterial Enzyme MurA

Identification and Biochemical Characterization of Pyrrolidinediones as Novel Inhibitors of the Bacterial Enzyme MurA

  • J Med Chem. 2022 Nov 10;65(21):14740-14763. doi: 10.1021/acs.jmedchem.2c01275.
Reem K Fathalla 1,  Wolfgang Fröhner 1,  Chantal D Bader 2 3,  Patrick D Fischer 1 4 5,  Charlotte Dahlem 6,  Deep Chatterjee 7,  Sebastian Mathea 7,  Alexandra K Kiemer 6,  Haribabu Arthanari 4 5,  Rolf Müller 2 3 8,  Mohammad Abdel-Halim 9,  Christian Ducho 1,  Matthias Engel 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
  • 2 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.
  • 3 German Center for Infection Research (DZIF), Inhoffenstraße 7, 38124 Braunschweig, Germany.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, 02215 Boston, Massachusetts, United States.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 02115 Boston, Massachusetts, United States.
  • 6 Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
  • 7 Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt/Main, Germany.
  • 8 Helmholtz International Lab for Antiinfectives, Campus E8 1, 66123 Saarbrücken, Germany.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
PMID: 36269107 DOI: 10.1021/acs.jmedchem.2c01275
Abstract

To develop novel Antibiotics, targeting the early steps of cell wall peptidoglycan biosynthesis seems to be a promising strategy that is still underutilized. MurA, the first Enzyme in this pathway, is targeted by the clinically used irreversible inhibitor fosfomycin. However, mutations in its binding site can cause Bacterial resistance. We herein report a series of novel reversible pyrrolidinedione-based MurA inhibitors that equally inhibit wild type (WT) MurA and the fosfomycin-resistant MurA C115D mutant, showing an additive effect with fosfomycin for the inhibition of WT MurA. For the most potent inhibitor 46 (IC50 = 4.5 μM), the mode of inhibition was analyzed using native mass spectrometry and protein NMR spectroscopy. The compound class was nontoxic against human cells and highly stable in human S9 fraction, human plasma, and Bacterial cell lysate. Taken together, this novel compound class might be further developed toward Antibiotic drug candidates that inhibit cell wall synthesis.

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