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.

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.

Shin WS; Nguyen ME; Bergstrom A; Jennings IR; Crowder MW; Muthyala R; Sham YY

Chemical Biology & Drug Design

2021

2021-06-20

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.

NEOMED College of Medicine

Department of Pharmaceutical Sciences

Jan to Aug list 2021