A family of indoles regulate virulence and Shiga toxin production in pathogenic E. coli.
A family of indoles regulate virulence and Shiga toxin production in pathogenic E. coli.
复制标题
DOI：
10.1371/journal.pone.0054456
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kalman D
中科院分区：
文献类型：
--
作者：
Bommarius B;Anyanful A;Izrayelit Y;Bhatt S;Cartwright E;Wang W;Swimm AI;Benian GM;Schroeder FC;Kalman D
肠致病性大肠埃希菌(EPEC)、肠出血性大肠杆菌(EHEC)和肠聚集性大肠杆菌(EAEC)是引起人类食物和水传播疾病的肠道病原体。利用生化方法和基于核磁共振的比较代谢组学，结合线虫秀丽线虫，我们开发了一种生物检测方法来鉴定这些病原体产生的分泌性小分子。我们确定了吲哚、吲哚-3-甲醛(ICA)和吲哚-3-乙酸(IAA)，这些因素只有结合在一起才足以杀死线虫。重要的是，虽然这些分子对线虫是致命的，但它们下调了几个对哺乳动物发病重要的细菌过程。这些包括运动性、生物膜的形成和志贺毒素的产生。已知一些致病性大肠杆菌菌株含有肠细胞消失位点(Lee)，它编码的毒力因子会导致哺乳动物的“附着和消失”(A/E)损伤，包括肌动蛋白基座的形成。我们发现，这些吲哚类化合物还下调Lee毒力因子的产生，并抑制哺乳动物细胞的基座形成。最后，在口服给药后，ICA抑制了致死性小鼠感染模型的毒力并促进了存活。总之，秀丽线虫模型与代谢组学相结合，有助于鉴定一类吲哚类化合物，这些化合物广泛调节大肠杆菌的生理和致病菌株的毒力。这些分子可能会使干扰细菌小分子信号的新疗法的开发成为可能。
Enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and enteroaggregative E. coli (EAEC) are intestinal pathogens that cause food and water-borne disease in humans. Using biochemical methods and NMR-based comparative metabolomics in conjunction with the nematode Caenorhabditis elegans, we developed a bioassay to identify secreted small molecules produced by these pathogens. We identified indole, indole-3-carboxaldehyde (ICA), and indole-3-acetic acid (IAA), as factors that only in combination are sufficient to kill C. elegans. Importantly, although lethal to C. elegans, these molecules downregulate several bacterial processes important for pathogenesis in mammals. These include motility, biofilm formation and production of Shiga toxins. Some pathogenic E. coli strains are known to contain a Locus of Enterocyte Effacement (LEE), which encodes virulence factors that cause “attaching and effacing” (A/E) lesions in mammals, including formation of actin pedestals. We found that these indole derivatives also downregulate production of LEE virulence factors and inhibit pedestal formation on mammalian cells. Finally, upon oral administration, ICA inhibited virulence and promoted survival in a lethal mouse infection model. In summary, the C. elegans model in conjunction with metabolomics has facilitated identification of a family of indole derivatives that broadly regulate physiology in E. coli, and virulence in pathogenic strains. These molecules may enable development of new therapeutics that interfere with bacterial small-molecule signaling.
登录
查看更多内容
影响因子：
30.3
作者：
Anyanful A;Easley KA;Benian GM;Kalman D
通讯作者：
Kalman D
影响因子：
21.3
作者：
Kalman, D;Weiner, OD;Bishop, JW
通讯作者：
Bishop, JW
影响因子：
3.6
作者：
Hirakawa, H;Inazumi, Y;Yamaguchi, A
通讯作者：
Yamaguchi, A
影响因子：
2.8
作者：
Kuczynska-Wisnik, Dorota;Matuszewska, Ewelina;Laskowska, Ewa
通讯作者：
Laskowska, Ewa
影响因子：
56.9
作者：
Kim, DH;Feinbaum, R;Ausubel, FM
通讯作者：
Ausubel, FM