2. Academic Validation
  3. Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria

Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria

  • Eur J Med Chem. 2024 Sep 27:280:116920. doi: 10.1016/j.ejmech.2024.116920.
Nour Ayoub 1,  Amit Upadhyay 2,  Arnaud Tête 3,  Nicolas Pietrancosta 4,  Hélène Munier-Lehmann 5,  Timothy P O'Sullivan 6
Affiliations

Affiliations

  • 1 Université Paris Cité, INSERM UMRS-1124, Institut Pasteur, Structural Biology and Chemistry Department, F-75006, Paris, France.
  • 2 School of Chemistry, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
  • 3 Université Paris Cité, INSERM UMRS-1124, F-75006, Paris, France.
  • 4 Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, F-75005, Paris, France; Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), F-75005, Paris, France.
  • 5 Université Paris Cité, INSERM UMRS-1124, Institut Pasteur, Structural Biology and Chemistry Department, F-75006, Paris, France. Electronic address: helene.munier-lehmann@pasteur.fr.
  • 6 School of Chemistry, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland. Electronic address: tim.osullivan@ucc.ie.
PMID: 39369481 DOI: 10.1016/j.ejmech.2024.116920
Abstract

Antimicrobial resistance poses a significant threat to global health, necessitating the development of novel therapeutic agents with unique mechanisms of action. Inosine 5'-monophosphate dehydrogenase (IMPDH), an essential Enzyme in guanine nucleotide biosynthesis, is a promising target for the discovery of new antimicrobial agents. High-throughput screening studies have previously identified several urea-based leads as potential inhibitors, although many of these are characterised by reduced chemical stability. In this work, we describe the design and synthesis of a series of heteroaryl-susbtituted analogues and the evaluation of their inhibitory potency against IMPDHs. Our screening targets ESKAPEE pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. Several analogues with submicromolar inhibitory potency are identified and show no inhibitory potency on human IMPDH nor cytotoxic effects on human cells. Kinetic studies revealed that these molecules act as noncompetitive inhibitors with respect to the substrates and ligand virtual docking simulations provided insights into the binding interactions at the interface of the NAD+ and IMP binding sites on IMPDH.

Keywords

Antibacterials; ESKAPEE bacteria; Heteroaryls; IMPDH; Inhibitors; Nucleotide metabolism.

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