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.

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journalArticle

1747-0285 1747-0277

NEOMED College of Pharmacy

Department of Pharmaceutical Sciences

June 2021 List