Discovery of Novel Inhibitors of Uridine Diphosphate- N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients

J Med Chem. 2022 Feb 10;65(3):2149-2173. doi: 10.1021/acs.jmedchem.1c01684. Epub 2022 Jan 26.


Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 μM (LE 0.35).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / mortality
  • Cystic Fibrosis / pathology
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Molecular Conformation
  • Molecular Docking Simulation
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / drug therapy
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology*
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Ligands
  • Pyrazoles
  • pyrazole
  • Oxidoreductases