1. Academic Validation
  2. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor

Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor

  • Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. doi: 10.1073/pnas.1205073109.
David E Ehmann 1 Haris Jahić Philip L Ross Rong-Fang Gu Jun Hu Gunther Kern Grant K Walkup Stewart L Fisher
Affiliations

Affiliation

  • 1 Infection Innovative Medicines Unit, AstraZeneca Research & Development Boston, Waltham, MA 02451, USA. david.ehmann@astrazeneca.com
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.

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