title: Fragment-based discovery of inhibitor scaffolds targeting the metallo-β-lactamases NDM-1 and VIM-2.
abstract: Metallo-β-lactamases (MBLs) render bacteria resistant to β-lactam antibiotics and are interesting drug targets to prevent the hydrolysis of β-lactam antibiotics. So far, there are no MBL inhibitors in clinical use and particularly the design of broad spectrum inhibitors targeting several MBLs has been difficult. In this study, we report four fragments inhibiting the clinically relevant New Delhi metallo-β-lactamase 1 (NDM-1) and Verona integron-encoded metallo-β-lactamase 2 (VIM-2). The fragments were identified from a library using an orthogonal screening strategy combining a surface plasmon resonance (SPR) based assay and an enzyme inhibition assay. The identified fragments showed dissociation constants (KD) ranging from 181 to 2100 μM. The binding mode of the fragments was explored using QM-polarized ligand docking. All four fragments represent interesting scaffolds for the design of broad-spectrum MBL inhibitors.
authors.affiliation: The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Tony
authors.initials: T
authors.lastname: Christopeit
authors.affiliation: The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address: hanna-kirsti.leiros@uit.no.
authors.forename: Hanna-Kirsti S
authors.initials: HK
authors.lastname: Leiros
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D065093:beta-Lactamase Inhibitors; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
keywords: Antibiotic resistance; Fragment screening; Metalloprotein; Molecular docking; Surface plasmon resonance (SPR)