Fragment-based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor

Metallo-β–lactamases (MBLs) are zinc-containing carbapenemases that inactivate a broad range of β–lactam antibiotics. There is a lack of β–lactamase inhibitors for restoring existing β–lactam antibiotics arsenals against common bacterial infections. Fragment-based screening of a non-specific metal chelator library demonstrates 8-hydroxyquinoline as a broad-spectrum nanomolar inhibitor against VIM-2 and NDM-1. A hit-based substructure search provided an early structure–activity relationship of 8-hydroxyquinolines and identified 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic β–lactamase inhibitor that can restore β–lactam activity against VIM-2-expressing E. coli. Molecular modeling further shed structural insight into its potential mode of binding within the dinuclear zinc active site. 8-Hydroxyquinoline-7-carboxylic acid is highly stable in human plasma and human liver microsomal study, making it an ideal lead candidate for further development.