12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Proceedings of the National Academy of Sciences of the United States of America
      Acylation, drug effects, Anti-Bacterial Agents, chemistry, metabolism, pharmacology, Azabicyclo Compounds, Drug Discovery, methods, Gram-Negative Bacterial Infections, drug therapy, Kinetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Molecular Structure, beta-Lactamase Inhibitors

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Comments

          Comment on this article