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

Woo Shik Shin, Megin E. Nguyen, Alexander Bergstrom, Isabella R. Jennings, Michael W. Crowder, Ramaiah Muthyala, Yuk Yin Sham

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)481-492
Number of pages12
JournalChemical Biology and Drug Design
Volume98
Issue number4
DOIs
StatePublished - Oct 2021

Bibliographical note

Funding Information:
Research support for Y.Y.S. and R.M. was provided by the University of Minnesota College of Pharmacy and Medical School. The University of Minnesota Supercomputing Institute provided all the necessary computational resources.

Publisher Copyright:
© 2021 John Wiley & Sons A/S.

Keywords

  • 8-hydroxyquinoline
  • carbapenemases
  • drug resistance
  • fragment-based screening
  • metallo beta-lactamase

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