Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD

• Published in: European journal of medicinal chemistry Vol. 90; pp. 351 - 359
• Main Authors: Allegretta, Giuseppe, Weidel, Elisabeth, Empting, Martin, Hartmann, Rolf W.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 27.01.2015; Elsevier
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - metabolism; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Catechols - chemical synthesis; Catechols - chemistry; Catechols - pharmacology; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HHQ; Life Sciences & Biomedicine; Pharmacology & Pharmacy; PqsD; Pseudomonas aeruginosa; Pseudomonas aeruginosa - enzymology; Quorum sensing; Quorum Sensing - drug effects; Science & Technology; SPR; Substrate Specificity; QS; BOP; CF; ACoA; IS; TFA; HHQ; HRMS; PQS; THF; PqsD; SPR; CoA; Pseudomonas aeruginosa; Quorum sensing; DMF; INFECTIONS; AERUGINOSA; SPECIFICITY; ACIDS; ENZYME; PSEUDOMONAS QUINOLONE SIGNAL; GENES; RESISTANCE; SURFACE-PLASMON RESONANCE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.11.055

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. [Display omitted] •Novel anti-quorum sensing inhibitors were developed by me-too approach.•The compounds showed promising activity in vitro and in cellulo.•The binding site of novel inhibitors was investigated via SPR.