Discovery of Novel Inhibitors of UDP-N- Acetylenolpyruvylglucosa- mine Reductase (MurB) from Pseudomonas aeruginosa, an opportun- istic infectious agent causing death in cystic fibrosis patients

Abstract

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 phe- nylpyrazole scaffold was shown by ITC to bind with an affinity of Kd = 2.9 mM (LE 0.23). Using a structure guided approach different substitutions were synthesised and the initial fragment was optimised to obtain a small molecule with Kd = 3.6 μM (LE 0.35).