Abstract
Shiga toxin, produced by a diverse group of Escherichia coli, uses a complex retrograde transport pathway in order to inactivate the ribosome of susceptible cells. Infection with the toxin is associated with dysentery, hemorrhagic colitis, and hemolytic uremic syndrome due to its ability to inhibit protein synthesis, ultimately killing the host cells. No effective treatment has been developed to inactivate and prevent complications of this toxin.
We undertook a novel screening approach to identify small molecule compounds that inhibit shiga toxin activity. Using a luciferase-based assay developed in our laboratory, a screen of approximately 16,000 compounds was performed. Of these, approximately two hundred potential inhibitors of shiga toxin were identified. We are currently characterizing each of these inhibitors with respect to their potency in inhibiting toxin and their toxicity toward human cells. Using immunofluorescence microscopy and other approaches, we will determine the point at which individual inhibitors block shiga toxin trafficking or function. Data will be presented on the most active of these novel compounds.
Using this new approach, we hope to identify small molecular compounds that block shiga toxin trafficking at several steps during its retrograde transport. These experiments will provide insight into the mechanism of toxin trafficking and potential strategies for developing therapeutic agents for toxin-associated disease.
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Debaun, M., Haslam, D. 31 A Novel Screening Technique for Detecting Small Molecule Inhibitors of Shiga Toxin Trafficking.. Pediatr Res 58, 821 (2005). https://doi.org/10.1203/00006450-200510000-00061
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DOI: https://doi.org/10.1203/00006450-200510000-00061