Fragment-Based Screening And Hit-Based Substructure Search: Rapid Discovery Of 8-Hydroxyquinoline-7-Carboxylic Acid As A Low-Cytotoxic, Nanomolar Metallo Beta-Lactamase Inhibitor

Metallo-beta-lactamases (MBLs) are zinc-containing carbapenemases that inactivate a broad range of beta-lactam antibiotics. There is a lack of beta-lactamase inhibitors for restoring existing beta-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 beta-lactamase inhibitor that can restore beta-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.