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  • Identification of five structurally unrelated quorum-sensing inhibitors of Pseudomonas aeruginosa from a natural-derivative database.

Identification of five structurally unrelated quorum-sensing inhibitors of Pseudomonas aeruginosa from a natural-derivative database.

Antimicrobial agents and chemotherapy (2013-09-05)
Sean Yang-Yi Tan, Song-Lin Chua, Yicai Chen, Scott A Rice, Staffan Kjelleberg, Thomas E Nielsen, Liang Yang, Michael Givskov
摘要

Bacteria communicate by means of small signal molecules in a process termed quorum sensing (QS). QS enables bacteria to organize their activities at the population level, including the coordinated secretion of virulence factors. Certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), have been shown to effectively block QS and subsequently attenuate the virulence of Pseudomonas aeruginosa, as well as increasing its susceptibility to both antibiotics and the immune system. In this study, a structure-based virtual screening (SB-VS) approach was used for the discovery of novel QSI candidates. Three-dimensional structures of 3,040 natural compounds and their derivatives were obtained, after which molecular docking was performed using the QS receptor LasR as a target. Based on docking scores and molecular masses, 22 compounds were purchased to determine their efficacies as quorum-sensing inhibitors. Using a live reporter assay for quorum sensing, 5 compounds were found to be able to inhibit QS-regulated gene expression in P. aeruginosa in a dose-dependent manner. The most promising compound, G1, was evaluated by isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis, and it was found to significantly affect the abundance of 46 proteins (19 were upregulated; 27 were downregulated) in P. aeruginosa PAO1. It specifically reduced the expression of several quorum-sensing-regulated virulence factors, such as protease IV, chitinase, and pyoverdine synthetases. G1 was also able to reduce extracellular DNA release and inhibited the secretion of the virulence factor, elastase, whose expression is regulated by LasR. These results demonstrate the utility of SB-VS for the discovery of target-specific QSIs.

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Sigma-Aldrich
弹性蛋白酶 来源于猪胰腺, Type I, ≥4.0 units/mg protein
Sigma-Aldrich
灰链霉菌来源几丁质酶, lyophilized powder (essentially salt free), ≥200 units/g solid
Sigma-Aldrich
弹性蛋白酶 来源于猪胰腺, lyophilized powder, suitable for cell culture
Sigma-Aldrich
壳质酶 来源于绿色木霉, lyophilized powder, ≥600 units/g solid
Sigma-Aldrich
弹性蛋白酶 来源于猪胰腺, Type IV, Protein 50-90 %, lyophilized powder, ≥4.0 units/mg protein (biuret)
Sigma-Aldrich
弹性蛋白酶 来源于猪胰腺, Type III, lyophilized powder, Protein 55-85 %, ≥4.0 units/mg protein