Crystal structures of the molecular class A β -lactamase TEM-171 and its complexes with tazobactam

The resistance of bacteria to β -lactam antibiotics is primarily caused by the production of β -lactamases. Here, novel crystal structures of the native β -lactamase TEM-171 and two complexes with the widely used inhibitor tazobactam are presented, alongside complementary data from UV spectroscopy and fluorescence quenching. The six chemically identical β -lactamase molecules in the crystallographic asymmetric unit displayed different degrees of disorder. The tazobactam intermediate was covalently bound to the catalytic Ser70 in the trans-enamine configuration. While the conformation of tazobactam in the first complex resembled that in published β -lactamase – tazobactam structures, in the second complex, which was obtained after longer soaking of the native crystals in the inhibitor solution, a new and previously unreported tazobactam conformation was observed. It is proposed that the two complexes correspond to different stages along the deacylation path of the acyl-enzyme intermediate. The results provide a novel structural basis for the rational design of new β -lactamase inhibitors.

Source: Acta Crystallographica Section D - June 7, 2022 Category: Biochemistry Authors: Grigorenko, V.G. Petrova, T.E. Carolan, C. Rubtsova, M.Y. Uporov, I.V. Pereira, J. Chojnowski, G. Samygina, V.R. Lamzin, V.S. Egorov, A.M. Tags: β -lactamase TEM-171 tazobactam intermediate antibiotic resistance enzyme inhibition crystal structure UV spectroscopy research papers Source Type: research