Discovery of chromene compounds as inhibitors of PvdQ acylase of Pseudomonas aeruginosa

The acquisition of iron is a crucial mechanism for the survival of pathogenic bacteria such as Pseudo-monas aeruginosa in eukaryotic hosts. The key iron chelator in this organism is the siderophore pyo-verdine, which was shown to be crucial for iron homeostasis. Pyoverdine is a non-ribosomal peptide with several maturation steps in the cytoplasm and others in the periplasmatic space. A key enzyme for its maturation is the acylase PvdQ. The inhibition of PvdQ stops the maturation of pyoverdine causing a significant imbalance in the iron homeostasis and hence can negatively influence the survival of P. aeruginosa. In this work, we successfully synthesized chromene-derived inhibitory molecules targeting PvdQ in a low micromolar range. In silico modeling as well as kinetic evaluations of the inhibitors suggest a competitive inhibition of the PvdQ function. Further, we evaluated the inhibitor in vivo on P. aeruginosa cells and report a dose-dependent reduction of pyoverdine formation. The compound also showed a protecting effect in a Galleria mellonella infection model. (C) 2022 The Author(s). Published by Elsevier Masson SAS on behalf of Institut Pasteur.