Small Molecule Inhibitors of Clostridium difficile Toxin B-Induced Cellular Damage. Issue 2 (19th February 2015)

• Record Type: Journal Article
• Authors: Tam, John; Beilhartz, Greg L.; Auger, Anick; Gupta, Pulkit; Therien, Alex G.; Melnyk, Roman A.
• Is Part Of: Chemistry & biology. Volume 22:Issue 2(2015)
• Page Start: 175
• Page End: 185
• Publication Date: 2015-02-19
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2014.12.010
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: 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. Highlights: Two homologous toxins, TcdA and TcdB, cause the symptoms of C. difficile disease A phenotypic assay of toxin-induced damage of human cells was developed Small molecule inhibitors blocking host processes and toxin action are identified Inhibitors uncover new disease biology and inform novel therapeutic strategies Abstract : Targeting the potent homologous toxins of Clostridium difficile is a promising therapeutic approach to treat the symptoms associated with infection. Tam et al. describe the identification of the first small molecule inhibitors that protect human cells by blocking receptor binding and directly inhibiting toxin enzyme activity.