Derivatives of the Cashew Nut Shell Liquid as Ligands of Pseudomonas aeruginosa Phenazine Protein D (PaPhzD).

Pseudomonas aeruginosa isochorismatase PhzD (PaPhzD) is key to the biosynthesis of pyocyanin (PYO), a virulence factor facilitating pathogen infection and survival within the host. To date, no ligands of PaPhzD have been reported. Leveraging the chemical similarity between anacardic acid derivatives and the enzyme's natural substrate, three compounds (2, 3, and 4) were identified as low to submicromolar PaPhzD ligands, while compounds 2 and 4 reduced pyocyanin production (Cohen'd = -2.56 and -2.69, respectively) and swarming motility (Cohen'd = -0.91 and -0.95, respectively) at 100 μM, without affecting bacterial growth or biofilm formation (p > 0.05). Our results suggest that compounds binding to PaPhzD or PPAR have distinct SAR requirements, suggesting that they represent a promising scaffold for developing PaPhzD inhibitors.