Progress toward inhibitors of metallo-β-lactamases

The global overuse of antibiotics has led to the emergence of drug-resistant pathogenic bacteria. Bacteria can combat beta-lactams by expressing beta-lactamases. Inhibitors of one class of beta-lactamase, the serine-beta-lactamases, are used clinically to prevent degradation of beta-lactam antibiotics. However, a second class of beta-lactamase, the metallo-beta-lactamases (MBLs), function by a different mechanism to serine-beta-lactamases and no inhibitors of MBLs have progressed to be used in the clinic. Bacteria that express MBLs are an increasingly important threat to human health. This review outlines various approaches taken to discover MBL inhibitors, with an emphasis on the different chemical classes of inhibitors. Recent progress, particularly new screening methods and the rational design of potent MBL inhibitors are discussed.