Metallo-beta-lactamases: two binding sites for one catalytic metal ion?

During the past few years the results from molecular biological, biochemical, chemical, physical and theoretical approaches expanded the knowledge about metallo-beta-lactamases considerably. The main reason for the attracted interest is a persisting medical problem. Bacteria expressing metallo-beta-lactamases can be resistant to treatment with all the known beta-lactam antibiotics, and they are additionally invulnerable to combined treatment with inhibitors for the wider-spread serine-beta-lactamases. However, clinically useful inhibitors for metallo-beta-lactamases are not yet available. In spite of the rapidly expanding knowledge base a central question is still controversially discussed: is it the mononuclear, the binuclear or the metal-free state which might serve as the physiologically relevant target for inhibitor design? A summary of the present views of the roles and coordination geometries of metal ion(s) in metallo-beta-lactamases is combined with a discussion of the possibly variable metal ion content under physiological conditions.