title: Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
abstract: A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), 66123 Saarbrücken, Germany.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Allegretta
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), 66123 Saarbrücken, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weidel
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), 66123 Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Empting
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), 66123 Saarbrücken, Germany; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), 66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D053038:Quorum Sensing / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D002396:Catechols; D004791:Enzyme Inhibitors; D000217:Acyltransferases; C020141:flavanone synthetase; C034221:catechol
keywords: HHQ; PqsD; Pseudomonas aeruginosa; Quorum sensing; SPR