Traditional Chinese Medicine Monomer Bakuchiol Attenuates the Pathogenicity of Pseudomonas aeruginosa via Targeting PqsR

As the antibiotic resistance of pathogens becomes increasingly severe, it is becoming more feasible to use methods that suppress the virulence of pathogens rather than exerting selective pressure on their growth. <i>Pseudomonas aeruginosa</i>, a dangerous opportunistic pathogen, infects hosts by producing multiple virulence factors, which are regulated by quorum-sensing (QS) systems, including the <i>las</i> systems, <i>rhl</i> systems, and <i>pqs</i> systems. This study used the chromosome <i>lacZ</i> transcription fusion reporter model to screen the traditional Chinese medicine monomer library and found that bakuchiol can effectively inhibit the <i>pqs</i> system and related virulence phenotypes of <i>P. aeruginosa</i>, including the production of virulence factors (pyocyanin, hydrogen cyanide, elastase, and lectin) and motility (swarming, swimming, and twitching motility) without affecting its growth. Subsequently, through genetic complementation analysis, we found that bakuchiol inhibited the function of the transcriptional activation protein PqsR of the <i>pqs</i> system in <i>P. aeruginosa</i> in a concentration-dependent manner. Furthermore, molecular dynamics simulation study results indicated that bakuchiol can target PqsR of the <i>pqs</i> system, thereby inhibiting the <i>pqs</i> system. Among the amino acids in PqsR, ALA-168 may be a key amino acid residue in the hydrophobic interaction between PqsR protein and bakuchiol. Finally, in vivo experiments demonstrated that bakuchiol attenuated the pathogenicity of <i>P. aeruginosa</i> to Chinese cabbage (<i>Brassica pekinensis</i>) and <i>Caenorhabditis elegans</i>. In summary, this study suggests that bakuchiol is an effective inhibitor that targets the <i>pqs</i> system of <i>P. aeruginosa</i>, providing a new strategy for addressing <i>P. aeruginosa</i> infections.