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Discovery of novel inhibitors of uridine diphosphate-n-acetylenolpyruvylglucosamine reductase (MurB) from Pseudomonas aeruginosa, an opportunistic infectious agent causing death in cystic fibrosis patients

DOI: 10.1021/acs.jmedchem.1c01684 DOI Help

Authors: Marta Acebron-Garcia-De-Eulate (University of Cambridge) , Joan Mayol-Llinàs (University of Cambridge) , Matthew T. O. Holland (University of Cambridge) , So Yeon Kim (University of Cambridge) , Karen P. Brown (University of Cambridge; Royal Papworth Hospital) , Chiara Marchetti (University of Cambridge) , Jeannine Hess (University of Cambridge) , Ornella Di Pietro (University of Cambridge) , Vitor Mendes (University of Cambridge) , Chris Abell (University of Cambridge) , R. Andres Floto (University of Cambridge; Royal Papworth Hospital) , Anthony G. Coyne (University of Cambridge) , Tom L. Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 48

State: Published (Approved)
Published: January 2022
Diamond Proposal Number(s): 18548

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 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).

Journal Keywords: Reaction products; Ligands; Crystal structure; Phenyls; Organic compounds

Diamond Keywords: Cystic Fibrosis; Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 27/01/2022 14:29

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)