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Chem Biol. 2015 Feb 19;22(2):175-85. doi: 10.1016/j.chembiol.2014.12.010. Epub 2015 Jan 22.

Small molecule inhibitors of Clostridium difficile toxin B-induced cellular damage.

Author information

1
Molecular Structure & Function, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
2
Merck & Co. Inc., 2000 Galloping Hill Road, K15, Kenilworth, NJ 07033, USA.
3
Molecular Structure & Function, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: roman.melnyk@sickkids.ca.

Abstract

Clostridium difficile causes life-threatening diarrhea through the actions of its homologous toxins TcdA and TcdB on human colonocytes. Therapeutic agents that block toxin-induced damage are urgently needed to prevent the harmful consequences of toxin action that are not addressed with current antibiotic-based treatments. Here, we developed an imaging-based phenotypic screen to identify small molecules that protected human cells from TcdB-induced cell rounding. A series of structurally diverse compounds with antitoxin activity were identified and found to act through one of a small subset of mechanisms, including direct binding and sequestration of TcdB, inhibition of endosomal maturation, and noncompetitive inhibition of the toxin glucosyltransferase activity. Distinct classes of inhibitors were used further to dissect the determinants of the toxin-mediated necrosis phenotype occurring at higher doses of toxin. These findings validate and inform novel targeting strategies for discovering small molecule agents to treat C. difficile infection.

PMID:
25619932
DOI:
10.1016/j.chembiol.2014.12.010
[Indexed for MEDLINE]
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