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J Biol Chem. 2013 Sep 27;288(39):27960-71. doi: 10.1074/jbc.M113.485979. Epub 2013 Aug 2.

Kinetics of avibactam inhibition against Class A, C, and D β-lactamases.

Author information

1
From the Infection Innovative Medicines Unit and the Discovery Sciences Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts 02451.

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.

KEYWORDS:

Antibiotics; Drug Discovery; Enzyme Inhibitors; Enzyme Kinetics; Mass Spectrometry (MS)

PMID:
23913691
PMCID:
PMC3784710
DOI:
10.1074/jbc.M113.485979
[Indexed for MEDLINE]
Free PMC Article
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