Abstract
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.
Original language | English |
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Pages (from-to) | 8388-8407 |
Number of pages | 20 |
Journal | Journal of Medicinal Chemistry |
Volume | 63 |
Issue number | 15 |
DOIs | |
Publication status | Published - 2020 Aug 13 |
Bibliographical note
Funding Information:This work was supported by the National Research Foundation of Korea (2019R1A6A1A03031807 and 2020R1A2C2005919 to Y.B.) and by Korea Ministry of Environment (MOE) (1485016734 to H.D.P.). The authors thank professor Joon-Hee Lee at Pusan National University for kindly providing QS reporter strains and professor You-Hee Cho at CHA University for kindly providing rhlR mutants.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery