Metallo‐β‐lactamase structure and function

Abstract

β-lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site which, in turn, is dependent on the subclass of β-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-β-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes.

Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site

“…These enzymes catalyze the hydrolysis of the amide bond in the ␤-lactam ring characteristic of this family of drugs (1)(2)(3)(4)(5). MBLs are metal-dependent hydrolases which generally use Zn(II) as a Lewis acid to activate a water molecule for the nucleophilic attack.…”

“…The Zn(II)-binding residues vary among different subclasses, giving rise to diverse metal site architectures and metal contents required for activity (1)(2)(3)(4)(5)(6). B1 and B3 MBLs are broad-spectrum enzymes that hydrolyze penicillins, cephalosporins, and carbapenems with a wide variety of in vitro catalytic efficiencies, displaying a broad range of resistance profiles in vivo (1)(2)(3)(4)(5)8). The di-Zn(II) form of B1 MBLs has been shown to be the active form in the bacterial periplasm, despite contradictory data obtained from in vitro studies (8)(9)(10).…”

“…Crystal structures of MBLs from the three subclasses have revealed that these enzymes present a common ␣␤/␤␣ sandwich fold, with the active site located within a groove at the interface between these two halves (1-6). The Zn(II)-binding residues vary among different subclasses, giving rise to diverse metal site architectures and metal contents required for activity (1)(2)(3)(4)(5)(6). B1 and B3 MBLs are broad-spectrum enzymes that hydrolyze penicillins, cephalosporins, and carbapenems with a wide variety of in vitro catalytic efficiencies, displaying a broad range of resistance profiles in vivo (1)(2)(3)(4)(5)8).…”

Characterization of the poxAB Operon Encoding a Class D Carbapenemase in Pseudomonas aeruginosa,

“…Class B or metallo-β-lactamases (MLBs) are often described as being a class apart since unlike their serine counterparts they require Zn +2 in their active site in order to hydrolyze β-lactams (456,457). They have a broad hydrolysis spectrum that includes the carbapenems and most often also penicillins and cephalosporins (456,461,463).…”

“…They have a broad hydrolysis spectrum that includes the carbapenems and most often also penicillins and cephalosporins (456,461,463). MLBs are resistant to inhibition by the commercially available serine β-lactamase inhibitors and are unable to hydrolyze the monobactam aztreonam (456,557).…”