Principles and current strategies targeting metallo-β-lactamase mediated antibacterial resistance

Resistance to β-lactam antibacterials is commonly associated with the production of the serine β-lactamases (SBLs) and/or metallo-β-lactamases (MBLs). Although clinically useful inhibitors for the SBLs have been developed, no equivalent inhibitors are available for the MBLs, which can hydrolyze almost all β-lactam antibiotics, including the so-called "last resort" carbapenems. It is still a challenging task to develop a clinically useful inhibitor that should be broad-spectrum targeting multiple clinically relevant MBL enzymes that differ in their active site features. This review provides a detailed description of interaction modes of substrates and small-molecule inhibitors with various MBL enzymes and highlights the importance of metal- and "anchor residue"-binding features to achieve broad-spectrum MBL inhibition. Recently emerging active site interference strategies include metal ion deprivation, metal ion replacement, and cysteine modification as challenging, but worth experimenting directions for inhibitor development. The metalloenzyme selectivity, metal-binding pharmacophore, and cellular permeability and accumulation should be properly considered in the further development of clinically useful inhibitors to combat MBL-mediated antibacterial resistance.