title: The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening.
abstract: The emergence of metallo-β-lactamases (MBLs) capable of hydrolysing a broad spectrum of β-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound Maybridge™ library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies.
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Vella
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Hussein
authors.forename: Eleanor W W
authors.initials: EW
authors.lastname: Leung
authors.forename: Daniel
authors.initials: D
authors.lastname: Clayton
authors.forename: David L
authors.initials: DL
authors.lastname: Ollis
authors.forename: Nataša
authors.initials: N
authors.lastname: Mitić
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schenk
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D020134:Catalytic Domain; D002511:Cephalosporins / Q000627:therapeutic use*; D003124:Colorimetry; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007711:Klebsiella pneumoniae / Q000201:enzymology; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D054852:Small Molecule Libraries / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D065093:beta-Lactamase Inhibitors; C034025:CENTA