Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

Sang Jin Nam; So Young Ham; Hongmok Kwon; Han Shin Kim; Suhyun Moon; Jeong Hoon Lee; Taehyeong Lim; Sang Hyun Son; Hee Deung Park; Youngjoo Byun

doi:10.1021/acs.jmedchem.0c00630

Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

Sang Jin Nam, So Young Ham, Hongmok Kwon, Han Shin Kim, Suhyun Moon, Jeong Hoon Lee, Taehyeong Lim, Sang Hyun Son, Hee Deung Park, Youngjoo Byun

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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
Pages (from-to)	8388-8407
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00630
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

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title = "Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections",

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. ",

author = "Nam, {Sang Jin} and Ham, {So Young} and Hongmok Kwon and Kim, {Han Shin} and Suhyun Moon and Lee, {Jeong Hoon} and Taehyeong Lim and Son, {Sang Hyun} and Park, {Hee Deung} and Youngjoo Byun",

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. ",

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doi = "10.1021/acs.jmedchem.0c00630",

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AU - Nam, Sang Jin

AU - Ham, So Young

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AU - Lee, Jeong Hoon

AU - Lim, Taehyeong

AU - Son, Sang Hyun

AU - Park, Hee Deung

AU - Byun, Youngjoo

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PY - 2020/8/13

Y1 - 2020/8/13

N2 - 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.

AB - 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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Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections

Abstract

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