, Volume 13, Issue 7, pp 1039-1053
Date: 22 Jul 2008

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

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Abstract

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

Graphical abstract

The production of metallo-β-lactamases by bacteria is becoming a serious threat to the clinical community because these enzymes are responsible for the development of antibiotic resistance to the commonly employed β-lactam antibiotics. To understand the mechanism of the hydrolysis of the β-lactam ring in the antibiotics by metallo-β-lactamases, a great deal of effort has been directed to the design and synthesis of biomimetic models for these enzymes. This review highlights some important contributions made by various research groups in the area of synthetic analogues of metallo-β-lactamases, with major emphasis on the role of dinuclear Zn(II) complexes in the hydrolysis of β-lactam antibiotics.