The global epidemiology and treatment of metallo-β-lactamase-producing gram-negative pathogens

Infections caused by metallo-β-lactamase (MBL)-producing gram-negative pathogens represent a formidable and emerging threat to public health. MBLs compromise the activity of carbapenems and many newly developed β-lactam/β-lactamase inhibitor agents, leaving few treatment options. Remarkably, these enzymes have disseminated globally at an unprecedented rate. Therapeutic management of MBL-producing pathogens remains a major challenge because the enzymes are not inhibited by currently available β-lactamase inhibitors, and most pathogens that harbour MBLs are equipped with mechanisms of resistance to all available antibiotic classes. Recent advances have elucidated the biochemical and structural function of diverse MBLs thereby improving the development of future antibiotics. In this review, we summarize the contemporary global epidemiology of clinically relevant MBLs, describe the molecular mechanisms driving their dissemination and evaluate current and emerging therapeutic strategies for infections caused by MBL-producing gram-negative pathogens including Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia.