A Family of Indoles Regulate Virulence and Shiga Toxin Production in Pathogenic E. coli
Open Access
- 23 January 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (1), e54456
- https://doi.org/10.1371/journal.pone.0054456
Abstract
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.Keywords
This publication has 51 references indexed in Scilit:
- NMR-spectroscopic analysis of mixtures: from structure to functionCurrent Opinion in Chemical Biology, 2011
- Interkingdom signaling between pathogenic bacteria and Caenorhabditis elegansTrends in Microbiology, 2010
- Bacterial charity work leads to population-wide resistanceNature, 2010
- Small Molecules That Modulate Quorum Sensing and Control Virulence inPseudomonas aeruginosaThe Journal of Organic Chemistry, 2010
- The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammationProceedings of the National Academy of Sciences of the United States of America, 2009
- Conditioning Protects C. elegans from Lethal Effects of Enteropathogenic E. coli by Activating Genes that Regulate Lifespan and Innate ImmunityCell Host & Microbe, 2009
- A shortcut to identifying small molecule signals that regulate behavior and development in Caenorhabditis elegansProceedings of the National Academy of Sciences of the United States of America, 2009
- The role of quorum sensing in chronic cystic fibrosisPseudomonas aeruginosainfectionsFEMS Microbiology Letters, 2009
- A Conserved p38 MAP Kinase Pathway in Caenorhabditis elegans Innate ImmunityScience, 2002
- A C. elegans mutant that lives twice as long as wild typeNature, 1993