Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors
Cheng Chen, Peter Oelschlaeger, Dongmei Wang, Hao Xu, Qian Wang, Cheng Wang, Aiguo Zhao, Ke‐Wu Yang
Abstract
Serine/metallo-carbapenemase-coproducing pathogens, often referred to as "superbugs", are a significant clinical problem. They hydrolyze nearly all available β-lactam antibiotics, especially carbapenems considered as last-resort antibiotics, seriously endangering efficacious antibacterial treatment. Despite the continuous global spread of carbapenem resistance, no dual-action inhibitors are available in therapy. This Perspective is the first systematic investigation of all chemotypes, modes of inhibition, and crystal structures of dual serine/metallo-carbapenemase inhibitors. An overview of the key strategy for designing dual serine/metallo-carbapenemase inhibitors and their mechanism of action is provided, as guiding rules for the development of clinically available dual inhibitors, coadministrated with carbapenems, to overcome the carbapenem resistance issue.