Abstract
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.
Original language | English |
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Article number | 396 |
Number of pages | 10 |
Journal | Journal of Antibiotics |
Volume | 11 |
Issue number | 3 |
DOIs | |
Publication status | Published - 16 Mar 2022 |
Bibliographical note
Funding Information:Funding: We thank the Medical Research Council (EP/L016044/1, MR/T016035/1), the Biotechnology and Biological Research Council (BB/S50676X/1), and the Ineos Oxford Institute for Antimicrobial Research for funding. T.R.M. was supported by the BBSRC (BB/M011224/1). This research was funded in whole, or in part, by the Wellcome Trust (grant no. 106244/Z/14/Z and no. 099141/Z/12/Z).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- carbapenems
- antimicrobial resistance
- metallo-β-lactamases
- serine-β-lactamases
- biapenem