Kinetics of Avibactam Inhibition against Class A, C, and D β-Lactamases

Citations Over TimeTop 10% of 2013 papers

Abstract

Avibactam is a non-β-lactam β-lactamase inhibitor with a spectrum of activity that includes β-lactamase enzymes of classes A, C, and selected D examples. In this work acylation and deacylation rates were measured against the clinically important enzymes CTX-M-15, KPC-2, Enterobacter cloacae AmpC, Pseudomonas aeruginosa AmpC, OXA-10, and OXA-48. The efficiency of acylation (k2/Ki) varied across the enzyme spectrum, from 1.1 × 10(1) m(-1)s(-1) for OXA-10 to 1.0 × 10(5) for CTX-M-15. Inhibition of OXA-10 was shown to follow the covalent reversible mechanism, and the acylated OXA-10 displayed the longest residence time for deacylation, with a half-life of greater than 5 days. Across multiple enzymes, acyl enzyme stability was assessed by mass spectrometry. These inhibited enzyme forms were stable to rearrangement or hydrolysis, with the exception of KPC-2. KPC-2 displayed a slow hydrolytic route that involved fragmentation of the acyl-avibactam complex. The identity of released degradation products was investigated, and a possible mechanism for the slow deacylation from KPC-2 is proposed.

Related Papers

• Biodegradation of Crude Oil in Contaminated Water by Local Isolates of Enterobacter cloacae(2014)
• Study on Detection of Enterobacter cloacae in Powdered Milk(2009)
• The clinical analysis of the 29 infantnewborn enterobacter cloacae septicaemia.(2008)
• Study on the genes of β-Lactamase in Enterobacter cloacae(2006)
• → Exemplar Abstract for Enterobacter cloacae (Jordan 1890) Hormaeche and Edwards 1960 (Approved Lists 1980) and Enterobacter cloacae cloacae (Jordan 1890) Hoffmann et al. 2005.(2009)