Document Type




Format of Original

12 p.

Publication Date



American Chemical Society

Source Publication

Journal of the American Chemical Society

Source ISSN


Original Item ID

doi: 10.1021/ja801169j


Metallo-β-lactamases hydrolyze most β-lactam antibiotics. The lack of a successful inhibitor for them is related to the previous failure to characterize a reaction intermediate with a clinically useful substrate. Stopped-flow experiments together with rapid freeze−quench EPR and Raman spectroscopies were used to characterize the reaction of Co(II)−BcII with imipenem. These studies show that Co(II)−BcII is able to hydrolyze imipenem in both the mono- and dinuclear forms. In contrast to the situation met for penicillin, the species that accumulates during turnover is an enzyme−intermediate adduct in which the β-lactam bond has already been cleaved. This intermediate is a metal-bound anionic species with a novel resonant structure that is stabilized by the metal ion at the DCH or Zn2 site. This species has been characterized based on its spectroscopic features. This represents a novel, previously unforeseen intermediate that is related to the chemical nature of carbapenems, as confirmed by the finding of a similar intermediate for meropenem. Since carbapenems are the only substrates cleaved by B1, B2, and B3 lactamases, identification of this intermediate could be exploited as a first step toward the design of transition-state-based inhibitors for all three classes of metallo-β-lactamases.


Accepted version. Journal of the American Chemical Society, Vol. 130, No. 47 (November 2008): 15852–15863. DOI. © 2008 American Chemical Society. Used with permission.

Brian Bennett was affiliated with Medical College of Wisconsin at the time of publication.

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