title: Interaction of Avibactam with Class B Metallo-β-Lactamases.
abstract: β-Lactamases are the most important mechanisms of resistance to the β-lactam antibacterials. There are two mechanistic classes of β-lactamases: the serine β-lactamases (SBLs) and the zinc-dependent metallo-β-lactamases (MBLs). Avibactam, the first clinically useful non-β-lactam β-lactamase inhibitor, is a broad-spectrum SBL inhibitor, which is used in combination with a cephalosporin antibiotic (ceftazidime). There are multiple reports on the interaction of avibactam with SBLs but few such studies with MBLs. We report biochemical and biophysical studies on the binding and reactivity of avibactam with representatives from all 3 MBL subfamilies (B1, B2, and B3). Avibactam has only limited or no activity versus MBL-mediated resistance in pathogens. Avibactam does not inhibit MBLs and binds only weakly to most of the MBLs tested; in some cases, avibactam undergoes slow hydrolysis of one of its urea N-CO bonds followed by loss of CO2, in a process different from that observed with the SBLs studied. The results suggest that while the evolution of MBLs that more efficiently catalyze avibactam hydrolysis should be anticipated, pursuing the development of dual-action SBL and MBL inhibitors based on the diazabicyclooctane core of avibactam may be productive.
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Martine I
authors.initials: MI
authors.lastname: Abboud
authors.affiliation: Laboratoire de Chimie Biologique Structurale (CBS), Département de Chimie, Université de Liège, Liège, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Damblon
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brem
authors.affiliation: Laboratory of Mass Spectrometry, GIGA-R-CART, Université de Liège, Liège, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Smargiasso
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège, Liège, Belgium.
authors.forename: Paola
authors.initials: P
authors.lastname: Mercuri
authors.affiliation: Chimie Analytique Inorganique, Département de Chimie, Université de Liège, Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilbert
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rydzik
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Timothy D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom christopher.schofield@chem.ox.ac.uk jmfrere@ulg.ac.be.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège, Liège, Belgium christopher.schofield@chem.ox.ac.uk jmfrere@ulg.ac.be.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Frère
mesh_terms: D053961:Azabicyclo Compounds / Q000378:metabolism / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D002442:Ceftazidime; C476155:beta-lactamase SPM-1, Pseudomonas aeruginosa; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1