Developing Gingerol-Based Analogs against Pseudomonas aeruginosa Infections

Pseudomonas aeruginosa (P. aeruginosa), 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 P. aeruginosa infections. Particularly, the rhl 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 P. aeruginosa. 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 5a substituted with phenyl group in the tail region was the most potent in various biological assessments, such as RhlR binding affinity, rhl gene expression, and virulence factor production of P. aeruginosa. Furthermore, compound 5a decreased the biofilm formation and pathogenicity of P. aeruginosa. Interestingly, compound 5a also influenced las system in addition to the rhl system. Taken together, compound 5a can be utilized as a potent compound for controlling P. aeruginosa infection.