Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2

Autor: Anka Lucic, Tika R. Malla, Karina Calvopiña, Catherine L. Tooke, Jürgen Brem, Michael A. McDonough, James Spencer, Christopher J. Schofield
Rok vydání: 2022
Předmět:
Zdroj: Antibiotics; Volume 11; Issue 3; Pages: 396
Lucic, A, Malla, T R, Calvopiña, K, Tooke, C L, Spencer, J & Brem, J 2022, ' Studies on the Reactions of Biapenem with VIM metallo β-lactamases and the serine-β-lactamase KPC-2 ', Journal of Antibiotics, vol. 11, no. 3, 396 . https://doi.org/10.3390/antibiotics11030396
ISSN: 2079-6382
Popis: Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2S)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2R)- and (2S)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2R)- and (2S)-imine products, with the thermodynamically favoured (2S)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2R)-imine and likely more stable (2S)-imine tautomer is of interest in developing improved carbapenems.
Databáze: OpenAIRE
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