Recent advances in β-lactamase inhibitor chemotypes and inhibition modes

The effectiveness of β-lactam antibiotics is increasingly influenced by serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), which can hydrolyze β-lactam antibiotics. The development of effective β-lactamase inhibitors is an important direction to extend use of β-lactam antibiotics. Although six SBL inhibitors have been approved for clinical use, but no MBL inhibitors or MBL/SBL dual-action inhibitors are available so far. Broad-spectrum targeting clinically relevant MBLs and SBLs is currently desirable, while it is not easy to achieve such a purpose owing to structural and mechanistic differences between MBLs and SBLs. In this review, we summarized recent advances of inhibitor chemotypes targeting MBLs and SBLs and their inhibition mechanisms, particularly including lead discovery and structural optimization strategies, with the aim to provide useful information for future efforts to develop new MBL and SBL inhibitors.