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|Title:||Identification of five structurally unrelated quorum-sensing inhibitors of pseudomonas aeruginosa from a natural-derivative database||Authors:||Tan, Sean Yang-Yi
Rice, Scott A.
Nielsen, Thomas Eiland
|Keywords:||DRNTU::Science::Biological sciences::Microbiology::Bacteria||Issue Date:||2013||Source:||Tan, S. Y.-Y., Chua, S.-L., Chen, Y., Rice, S. A., Kjelleberg, S., Nielsen, T. E., et al. (2013). Identification of five structurally unrelated quorum-sensing inhibitors of pseudomonas aeruginosa from a natural-derivative database. Antimicrobial agents and chemotherapy, 57(11), 5629-5641.||Series/Report no.:||Antimicrobial Agents and Chemotherapy||Abstract:||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.||URI:||https://hdl.handle.net/10356/106210
|ISSN:||0066-4804||DOI:||10.1128/AAC.00955-13||Rights:||© 2013 American Society for Microbiology. This paper was published in Antimicrobial Agents and Chemotherapy and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The published version is available at: [http://dx.doi.org/10.1128/AAC.00955-13]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
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