title: Discovery of a novel covalent non-β-lactam inhibitor of the metallo-β-lactamase NDM-1.
abstract: The inhibition of metallo-β-lactamases (MBL) can prevent the hydrolysis of β-lactam antibiotics and hence is a promising strategy for the treatment of antibiotic resistant infections. In this study, we present a novel reversible covalent inhibitor of the clinically relevant MBL New Delhi metallo-β-lactamase 1 (NDM-1). Electrospray ionization-mass spectrometry (ESI-MS) and single site directed mutagenesis were used to show that the inhibitor forms a covalent bond with Lys224 in the active site of NDM-1. The inhibitor was further characterized using an enzyme inhibition assay, a surface plasmon resonance (SPR) based biosensor assay and covalent docking. The determined inhibition constant (KI(∗)) was 580nM and the inhibition constant for the initial complex (KI) was 76μM. To our knowledge, this inhibitor is the first example for a reversible covalent non-β-lactam inhibitor targeting NDM-1 and a promising starting point for the design of potent covalent 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: Norut Northern Research Institute, PO Box 6434, N-9294 Tromsø, Norway.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Albert
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: HS
authors.lastname: Leiros
mesh_terms: D002216:Captopril / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D000077731:Meropenem; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D021241:Spectrometry, Mass, Electrospray Ionization; D020349:Surface Plasmon Resonance; D013845:Thienamycins / Q000737:chemistry / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D002216:Captopril; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem
keywords: 3-Formylchromone; Antibiotic resistance; Covalent docking; Mass spectrometry; Surface Plasmon Resonance (SPR)