The Continuing Challenge of Metallo-beta-Lactamase Inhibition: Mechanism Matters

摘要

Metallo-beta-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all beta-lactann-containing antibiotics. These 'lifesaving drugs' constitute 50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.