Validation of PqsD as an anti-biofilm target in Pseudomonas aeruginosa by development of small-molecule inhibitors

J Am Chem Soc. 2012 Oct 3;134(39):16143-6. doi: 10.1021/ja3072397. Epub 2012 Sep 24.

Abstract

2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors. Simplification and rigidization led to fragments with high ligand efficiencies. These small molecules repress HHQ and PQS production and biofilm formation in P. aeruginosa. This validates PqsD as a target for the development of anti-infectives.

MeSH terms

  • Biofilms / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Hydroxyquinolines / metabolism
  • Pseudomonas aeruginosa / cytology
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology*
  • Pseudomonas aeruginosa / physiology*
  • Quorum Sensing / drug effects
  • Small Molecule Libraries / pharmacology*

Substances

  • Enzyme Inhibitors
  • Hydroxyquinolines
  • Small Molecule Libraries
  • MY 12-62c