Zinc and antibiotic resistance: metallo-beta-lactamases and their synthetic analogues

Antibiotic resistance to clinically employed beta-lactam antibiotics currently poses a very serious threat to the clinical community. The origin of this resistance is the expression of several beta-lactamases that effectively hydrolyze the amide bond in beta-lactam compounds. These beta-lactamases are classified into two major categories: serine beta-lactamases and metallo-beta-lactamases. The metalloenzymes use one or two zinc ions in their active sites to catalyze the hydrolysis of all classes of beta-lactam antibiotics, including carbapenems. As there is no clinically useful inhibitor for the metallo-beta-lactamases, it is important to understand the mechanism by which these enzymes catalyze the hydrolysis of antibiotics. In this regard, the development of synthetic analogues will be very useful in understanding the mechanism of action of metallo-beta-lactamases. This review highlights some important contributions made by various research groups in the area of synthetic analogues of metallo-beta-lactamases, with major emphasis on the role of dinuclear Zn(II) complexes in the hydrolysis of beta-lactam antibiotics.