Cross-subclass metallo-β-lactamase inhibitors: From structural and catalytic commonalities guiding design

Abstract

The emergence of antibiotic resistance mediated by metallo-β-lactamases (MβLs) has become a problem due to its diverse and widespread resistance characteristics. Research on broad-spectrum inhibitors has become an important issue. This review summarized the reported metallo-β-lactamases inhibitors (MβLIs) with cross-class activity, as well as four practical design strategies for developing cross-subclass MβLIs. It provides a detailed analysis of current inhibitors, covering their chemical structures, mechanisms, and cross-class activities. Four design strategies are discussed: i) substrate simulation strategy, ii) combining metal-chelating motifs strategy, iii) covalent inhibition strategy, and iv) metal ion replacement strategy. These strategies offer insights into developing effective cross-subclass MβLIs to combat the increasing prevalence of resistant pathogens.