2. Academic Validation
  3. Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

  • J Med Chem. 2020 Aug 13;63(15):8388-8407. doi: 10.1021/acs.jmedchem.0c00630.
SangJin Nam 1,  So-Young Ham 2,  Hongmok Kwon 1,  Han-Shin Kim 3,  Suhyun Moon 1,  Jeong-Hoon Lee 2,  Taehyeong Lim 1,  Sang-Hyun Son 1,  Hee-Deung Park 2 4,  Youngjoo Byun 1 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 30019, Republic of Korea.
  • 2 School of Civil, Environmental and Architectural Engineering, Korea University, 145 Anam-ro, Seongbuk-Gu, Seoul 02841, Republic of Korea.
  • 3 Korean Peninsula Infrastructure Cooperation Team, Korea Institute of Civil Engineering and Building Technology (KICT), Goyang-si, Gyeonggi-do 10223, Republic of Korea.
  • 4 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-Gu, Seoul 02841, Republic of Korea.
  • 5 Biomedical Research Center, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
PMID: 32696644 DOI: 10.1021/acs.jmedchem.0c00630
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.

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