Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic human pathogen
that forms biofilms and produces virulence factors via quorum sensing (QS). Blocking the QS system in P.
aeruginosa is an excellent strategy to reduce biofilm
formation and the production of virulence factors. RhlR plays an essential
role in the QS system of P. aeruginosa. We synthesized 55 analogues based on the chemical structure of
4-gingerol and evaluated their RhlR inhibitory activities using the
cell-based reporter strain assay. Comprehensive structure–activity
relationship studies identified the alkynyl ketone 30 as the most potent RhlR antagonist. This compound displayed selective
RhlR antagonism over LasR and PqsR, strong inhibition of biofilm formation,
and reduced production of virulence factors in P. aeruginosa. Furthermore, the survival rate of Tenebrio molitor larvae treated with 30 in vivo greatly
improved. Therefore, compound 30, a pure RhlR antagonist,
can be utilized for developing QS-modulating molecules in the control
of P. aeruginosa infections.