Studies on the Reactions of Biapenem with VIM Metallo ß-Lactamases and the Serine ß-Lactamase KPC-2.
Antibiotics (Basel)
; 11(3)2022 Mar 16.
Article
em En
| MEDLINE
| ID: mdl-35326858
ABSTRACT
Carbapenems are important antibacterials and are both substrates and inhibitors of some ß-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-ß-lactamases VIM-1 and VIM-2 and the class A serine-ß-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the ß-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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Antibiotics (Basel)
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido