title: Validation of PqsD as an anti-biofilm target in Pseudomonas aeruginosa by development of small-molecule inhibitors.
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.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C23, 66123 Saarbrücken, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Storz
authors.forename: Christine K
authors.initials: CK
authors.lastname: Maurer
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wagner
authors.forename: Christian
authors.initials: C
authors.lastname: Brengel
authors.forename: Johannes C
authors.initials: JC
authors.lastname: de Jong
authors.forename: Simon
authors.initials: S
authors.lastname: Lucas
authors.forename: Mathias
authors.initials: M
authors.lastname: Müsken
authors.forename: Susanne
authors.initials: S
authors.lastname: Häussler
authors.forename: Anke
authors.initials: A
authors.lastname: Steinbach
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D018441:Biofilms / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006912:Hydroxyquinolines / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D053038:Quorum Sensing / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D054852:Small Molecule Libraries; C049991:MY 12-62c