Solution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid

Metallo-β-lactamases, enzymes which inactivate β-lactam
antibiotics, are of increasing biological and clinical significance
as a source of antibiotic resistance in pathogenic bacteria.
In the present study we describe the high-resolution solution
NMR structures of the Bacillus cereus metallo-β-lactamase
BcII and of its complex with R-thiomandelic acid, a broadspectrum
inhibitor of metallo-β-lactamases. This is the first
reported solution structure of any metallo-β-lactamase. There are
differences between the solution structure of the free enzyme
and previously reported crystal structures in the loops flanking
the active site, which are important for substrate and inhibitor
binding and catalysis. The binding of R-thiomandelic acid and
the roles of active-site residues are defined in detail. Changes
in the enzyme structure upon inhibitor binding clarify the role
of the mobile β3–β4 loop. Comparisons with other metallo-β-
lactamases highlight the roles of individual amino-acid residues in
the active site and the β3–β4 loop in inhibitor binding and provide
information on the basis of structure–activity relationships among
metallo-β-lactamase inhibitors.