Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor
| Autor: | Haris Jahic, Stewart L. Fisher, Gunther Kern, David E. Ehmann, Rong-Fang Gu, Jun Hu, Philip L. Ross, Grant K. Walkup |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Acylation Avibactam Mass Spectrometry beta-Lactamases Hydrolysis chemistry.chemical_compound Drug Discovery medicine chemistry.chemical_classification Vaborbactam Multidisciplinary Molecular Structure Biological Sciences Ceftazidime/avibactam Anti-Bacterial Agents Kinetics Enzyme chemistry Covalent bond Lactam Gram-Negative Bacterial Infections beta-Lactamase Inhibitors Azabicyclo Compounds medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 109:11663-11668 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|