Discovery of Antagonists of PqsR, a Key Player in 2-Alkyl-4-quinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa

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• 作者：Cenbin Lu¹ ; Benjamin Kirsch¹ ; Christina Zimmer¹ ; Johannes  ; C. de  ; Jong¹ ; Claudia Henn¹ ; Christine  ; K. Maurer¹ ; Mathias Mü ; sken² ; Susanne Hä ; ussler² ; ³ ; Anke Steinbach¹ ; ^{anke.steinbach@helmholtz-hzi.de} ; Rolf  ; W. Hartmann¹ ; ⁴ ; ^{rolf.hartmann@helmholtz-hzi.de}
• 刊名：Chemistry & Biology
• 出版年：2012
• 出版时间：23 March, 2012
• 年：2012
• 卷：19
• 期：3
• 页码：381-390
• 全文大小：632 K

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Summary

The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P.?aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In?vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K_d,app of compound 20: 7?nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P.?aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.