The global overuse of antibiotics has led to the emergence of drug-resistant pathogenic bacteria. Bacteria can combat β-lactams by expressing β-lactamases. Inhibitors of one class of β-lactamase, the serine-β-lactamases, are used clinically to prevent degradation of β-lactam antibiotics. However, a second class of β-lactamase, the metallo-β-lactamases (MBLs), function by a different mechanism to serine-β-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.

A number of captopril analogues were synthesised and tested as inhibitors of the metallo-β-lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.

A SAR study on derivatives of 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile 5a revealed that the 3-carbonitrile group, vicinal 4,5-diphenyl and N-benzyl side chains of the pyrrole are important for the inhibitory potencies of these compounds against members representing the three main subclasses of metallo-β-lactamases (MBLs), i.e. IMP-1 (representing the B1 subgroup), CphA (B2) and AIM-1 (B3). Coupling of 5a with a series of acyl chlorides and anhydrides led to the discovery of two N-acylamide derivatives, 10 and 11, as the two most potent IMP-1 inhibitors in this series. However, these compounds are less effective towards CphA and AIM-1. The N-benzoyl derivative of 5a retained potent in vitro activity against each of MBLs tested (with inhibition constants in the low μM range). Importantly, this compound also significantly enhanced the sensitivity of IMP-1, CphA- or AIM-1-producing cell cultures towards meropenem. This compound presents a promising starting point for the development of a universal MBL inhibitor, targeting members of each of the major subgroups of this family of enzymes.

The structure-activity-relationship (SAR) study of pyrrole 65 led to the successful identification of two potent IMP-1 inhibitors, 93 and 99, with a 14-to 17-fold increase in IMP-1 inhibitory potency as compared to pyrrole 65. However, synthetic modification of the 3-carbonitrile group of 65, or deletion of the N-benzyl chain resulted in a significant loss of IMP-1 inhibitory activity. IIIThe SAR study of thiazolidine 120a resulted in the discovery of the mercapto-amide-linked thiazolidine, 124a with a 20-fold improvement in IMP-1 inhibitory activity as compared to 120a. The extension of this study led to the identification of a highly potent thiazolidine derivative, 124g with IMP-1 inhibitory potency in the sub-micromolar range.IV