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
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Abstract
Pseudomonas aeruginosa employs a
characteristic <i>pqs</i> 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 <i>ortho</i> to the
amide and 3′-sulfonamide are essential for binding. Introduction
of substituents in the anthranilic part of the molecule resulted in
compounds with IC<sub>50</sub> 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