Developing Gingerol-Based Analogs against <i>Pseudomonas aeruginosa</i> Infections

<i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>), a Gram-negative opportunistic pathogen, produces virulent factors and forms biofilms through a quorum sensing (QS) mechanism. Modulating QS networks is considered an effective strategy for treating <i>P. aeruginosa</i> infections. Particularly, the <i>rhl</i> system, one of the QS networks, can be a potential target in treating patients with chronic infections. We previously discovered that gingerol acts as a RhlR antagonist of <i>P. aeruginosa</i>. Based on the chemical structure of gingerol, we have designed and synthesized gingerol derivatives by introducing various functional groups in the middle and tail regions. A comprehensive structure-activity relationship study showed that compound <b>5a</b> substituted with phenyl group in the tail region was the most potent in various biological assessments, such as RhlR binding affinity, <i>rhl</i> gene expression, and virulence factor production of <i>P. aeruginosa</i>. Furthermore, compound <b>5a</b> decreased the biofilm formation and pathogenicity of <i>P. aeruginosa</i>. Interestingly, compound <b>5a</b> also influenced <i>las</i> system in addition to the <i>rhl</i> system. Taken together, compound <b>5a</b> can be utilized as a potent compound for controlling <i>P. aeruginosa</i> infection.