Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors

摘要

Serine/metallo-carbapenemase-coproducing pathogens, often re-ferred to as"superbugs", are a significant clinical problem. They hydrolyze nearlyall available beta-lactam antibiotics, especially carbapenems considered as last-resortantibiotics, seriously endangering efficacious antibacterial treatment. Despite thecontinuous global spread of carbapenem resistance, no dual-action inhibitors areavailable in therapy. This Perspective is thefirst systematic investigation of allchemotypes, modes of inhibition, and crystal structures of dual serine/metallo-carbapenemase inhibitors. An overview of the key strategy for designing dualserine/metallo-carbapenemase inhibitors and their mechanism of action isprovided, as guiding rules for the development of clinically available dualinhibitors, coadministrated with carbapenems, to overcome the carbapenemresistance issue.