Development of irreversible inhibitors forβ-lactam inactived enzyme, metallo-β-lactamase

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IMP-1 metallo-β-lactamase is a dinuclear Zn(II) enzyme that catalyzes the hydrolysis and inactivation of mostβ-lactams including carbapenems, and is involved in one of the mechanisms for generating clinical resistance to antibiotics in pathogenic bacteria. We investigated the metal preferences of Zn(II) and Co(II) for the apo-enzyme of IMP-1 metallo-β-lactamase, apo-IMP-1, which contains a dinuclear metal binding site(the Zn1 and Zn2 sites), by UV-visible spectroscopy. The UV-visible spectrum of apo-IMP-1 containing 1 equiv. of Co(II) and 1 equiv. of Zn(II) showed a high preference of Zn(II) for the Zn1 site compared to Co(II). The interaction of IMP-1 metallo-β-lactamase with mercaptoacetic acid was also investigated using Co(II)-substituted IMP-1 and UV-visible spectroscopy. Possible metal binding modes of Co(II) or Zn(II) to the dinucelar metal binding site in apo-IMP-1 and of mercaptoacetic acid to Co(II)-substituted IMP-1 are proposed.