Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients.
Holland, Matthew TO
Kim, So Yeon
Brown, Karen P
Di Pietro, Ornella
Floto, R Andres
Blundell, Tom L
J Med Chem
American Chemical Society (ACS)
MetadataShow full item record
Acebrón-García-de-Eulate, M., Mayol-Llinàs, J., Holland, M. T., Kim, S. Y., Brown, K. P., Marchetti, C., Hess, J., et al. (2022). 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 https://doi.org/10.1021/acs.jmedchem.1c01684
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).
Anti-Bacterial Agents, Bacterial Proteins, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Cystic Fibrosis, Drug Evaluation, Preclinical, Humans, Ligands, Molecular Conformation, Molecular Docking Simulation, Oxidoreductases, Pseudomonas Infections, Pseudomonas aeruginosa, Pyrazoles
M.A.G.D.E. was supported by American leprosy Missions Grant (G88726). J.M.L., S.Y.K. and O.D.P. were funded by the Cystic Fibrosis Trust and Fondation Botnar (Grant No. 6063). C.M. was funded by the Bill and Melinda Gates Foundation, Hit-TB (OPP1024021). J.H. was funded by the Swiss National Science Foundation (SNSF Early PostDoc. Mobility Fellowship P2ZHP2_164947) and the Marie Curie Research Grant Scheme, EU H2020 Framework Programme (H2020-MSCA-IF-2017, ID: 789607). V.M. was funded by the Bill and Melinda Gates Foun- dation, Hit-TB (OPP1024021) and SHORTEN-TB (OPP1158806). KPB and RAF were funded by NIHR Cambridge Biomedical Research Centre. CA, RAF and TLB by the UK Cystic Fibrosis Trust (SRC010). RAF was funded by the Well- come Trust 107032AIA. And RAF and TLB were founded by the UK Cystic Fibrosis Trust (Innovation Hub grant 001).
Cystic Fibrosis Trust (IH 001)
Wellcome Trust (107032/B/15/Z)
European Commission Horizon 2020 (H2020) Marie Sklodowska-Curie actions (789607)
External DOI: https://doi.org/10.1021/acs.jmedchem.1c01684
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330264
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