Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor.
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Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL
Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor.
Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. doi: 10.1073/pnas.1205073109. Epub 2012 Jul 2.
- PubMed ID
- 22753474 [ View in PubMed]
- Abstract
Avibactam is a beta-lactamase inhibitor that is in clinical development, combined with beta-lactam partners, for the treatment of bacterial infections comprising gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a beta-lactam core but maintains the capacity to covalently acylate its beta-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 beta-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 beta-lactamase inhibitors.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Avibactam Beta-lactamase TEM Protein Escherichia coli YesInhibitorDetails