title: Structure optimization of 2-benzamidobenzoic acids as PqsD inhibitors for Pseudomonas aeruginosa infections and elucidation of binding mode by SPR, STD NMR, and molecular docking.
abstract: Pseudomonas aeruginosa employs a characteristic pqs quorum sensing (QS) system that functions via the signal molecules PQS and its precursor HHQ. They control the production of a number of virulence factors and biofilm formation. Recently, we have shown that sulfonamide substituted 2-benzamidobenzoic acids, which are known FabH inhibitors, are also able to inhibit PqsD, the enzyme catalyzing the last and key step in the biosynthesis of HHQ. Here, we describe the further optimization and characterization of this class of compounds as PqsD inhibitors. Structural modifications showed that both the carboxylic acid ortho to the amide and 3'-sulfonamide are essential for binding. Introduction of substituents in the anthranilic part of the molecule resulted in compounds with IC50 values in the low micromolar range. Binding mode investigations by SPR with wild-type and mutated PqsD revealed that this compound class does not bind into the active center of PqsD but in the ACoA channel, preventing the substrate from accessing the active site. This binding mode was further confirmed by docking studies and STD NMR.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) , Department of Drug Design and Optimization, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weidel
authors.forename: Johannes C
authors.initials: JC
authors.lastname: de Jong
authors.forename: Christian
authors.initials: C
authors.lastname: Brengel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Storz
authors.forename: Andrea
authors.initials: A
authors.lastname: Braunshausen
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Alberto
authors.initials: A
authors.lastname: Plaza
authors.forename: Anke
authors.initials: A
authors.lastname: Steinbach
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D042462:4-Quinolones / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D015363:Quinolones / Q000378:metabolism; D053038:Quorum Sensing; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; C528166:2-heptyl-4-quinolone; D042462:4-Quinolones; D001426:Bacterial Proteins; D001549:Benzamides; D001565:Benzoates; D004791:Enzyme Inhibitors; D015363:Quinolones; D013449:Sulfonamides; D014157:Transcription Factors