Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline

Abstract

Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance in vivo, under zinc limitation, than in vitro Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.

Keywords: drug development; metallo-β-lactamase; metalloenzymes; pharmacology; treatment.

FIG 1

Amino acid residues that bind zinc at the active sites of B1, B2, and B3 MBLs. (A) Crystal structures of B1 enzymes, including IMP, VIM, NDM, and B. fragilis CcrA, reveal two zinc-binding sites (Zn1 and Zn2). The Zn1 site contains three histidine residues (His116, His118, and His196), whereas the ligands for the Zn2 site are aspartic acid (Asp120), cysteine (Cys221), and histidine (His263). (B and C) There is only one zinc ion in the active site of the Aeromonas hydrophila enzyme (subclass B2) (B) and two in the active site S. maltophilia enzyme (subclass B3) (C). (Republished with permission from reference .)

FIG 2

Global distribution of acquired MBLs.