Identification of products of inhibition of GES-2 beta-lactamase by tazobactam by x-ray crystallography and spectrometry.

ABSTRACT: The GES-2 ?-lactamase is a class A carbapenemase, the emergence of which in clinically important bacterial pathogens is a disconcerting development as the enzyme confers resistance to carbapenem antibiotics. Tazobactam is a clinically used inhibitor of class A ?-lactamases, which inhibits the GES-2 enzyme effectively, restoring susceptibility to ?-lactam antibiotics. We have investigated the details of the mechanism of inhibition of the GES-2 enzyme by tazobactam. By the use of UV spectrometry, mass spectroscopy, and x-ray crystallography, we have documented and identified the involvement of a total of seven distinct GES-2·tazobactam complexes and one product of the hydrolysis of tazobactam that contribute to the inhibition profile. The x-ray structures for the GES-2 enzyme are for both the native (1.45 Å) and the inhibited complex with tazobactam (1.65 Å). This is the first such structure of a carbapenemase in complex with a clinically important ?-lactam inhibitor, shedding light on the structural implications for the inhibition process.

SUBMITTER: Frase H 

PROVIDER: S-EPMC3077639 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature