title: Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor.
abstract: Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the off-rate for deacylation. The deacylation off-rate was 0.045 min(-1), which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.
authors: Infection Innovative Medicines Unit, AstraZeneca Research & Development Boston, Waltham, MA 02451, USA. david.ehmann@astrazeneca.com
authors: David E
authors: DE
authors: Ehmann
authors: Haris
authors: H
authors: Jahić
authors: Philip L
authors: PL
authors: Ross
authors: Rong-Fang
authors: RF
authors: Gu
authors: Jun
authors: J
authors: Hu
authors: Gunther
authors: G
authors: Kern
authors: Grant K
authors: GK
authors: Walkup
authors: Stewart L
authors: SL
authors: Fisher
mesh_terms: D000215:Acylation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1