A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation

被引:574
|
作者
O'Loughlin, Colleen T. [1 ]
Miller, Laura C. [2 ]
Siryaporn, Albert [1 ]
Drescher, Knut [1 ,3 ]
Semmelhack, Martin F. [2 ]
Bassler, Bonnie L. [1 ,4 ]
机构
[1] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
[2] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA
[3] Princeton Univ, Dept Mech & Aerosp Engn, Princeton, NJ 08544 USA
[4] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
EXPRESSION; MECHANISMS; PYOCYANIN; INFECTION; BACTERIA; NETWORK; SYSTEM; GENES; RHLR; LUXR;
D O I
10.1073/pnas.1316981110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited bymBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.
引用
收藏
页码:17981 / 17986
页数:6
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