期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2012
卷号：109
期号：29
页码：11663-11668
DOI：10.1073/pnas.1205073109
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
