• Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa.

      Lu, Cenbin; Kirsch, Benjamin; Zimmer, Christina; de Jong, Johannes C; Henn, Claudia; Maurer, Christine K; Müsken, Mathias; Häussler, Susanne; Steinbach, Anke; Hartmann, Rolf W; Helmholtz Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany. (2012-03-23)
      The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.
    • Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine.

      Monjas, Leticia; Swier, Lotteke J Y M; Setyawati, Inda; Slotboom, Dirk J; Hirsch, Anna K H; Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E9.1, 66123 Saarbrücken, Germany. (2017-10-20)
      We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.