Harder than Metal: Challenging Antimicrobial Resistance with Metallo-β-lactamase Inhibitors

The spread of antimicrobial resistance (AMR) represents a major global health challenge, weakening the efficacy of antibiotics such as β-lactams, which are, nowadays, the most widely used drugs for treating bacterial infections. Among the different resistance mechanisms, the production of β-lactamases, particularly metallo-β-lactamases (MBLs), significantly compromises the activity of these antibiotics. Despite progress in developing serine-β-lactamase inhibitors (SBLi), no MBL inhibitors (MBLi) are currently available in clinical practice. This Perspective provides an outlook on AMR mechanisms, with a focus on the expression of MBL enzymes, and showcases the main classes of MBLi proposed to date, which mainly act through coordination of the zinc ion(s) populating the active site of the MBL class of enzymes. Furthermore, the Perspective describes current strategies aimed at overcoming the limited cellular permeability of MBLi, one of the major hurdles preventing their translation into clinical studies.