期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 1, 页码 17-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2018.10.002
关键词
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资金
- Swiss National Science Foundation [205321_141263]
- Canadian Institutes of Health Research (CIHR)
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2015-05364]
- Crohn's and Colitis Canada grant
- Swiss National Science Foundation (SNF) [205321_141263] Funding Source: Swiss National Science Foundation (SNF)
Clostridium difficile causes increasing numbers of life-threatening intestinal infections. Symptoms associated with C. difficile infection (CDI) are mediated by secreted protein toxins, whose virulence is modulated by intracellular auto-proteolysis following allosteric activation of their protease domains by inositol hexakisphosphate (IP6). Here, we explore the possibility of inactivating the C. difficile toxin B (TcdB) by triggering its auto-proteolysis in the gut lumen prior to cell uptake using gain-of-function small molecules. We anticipated that high calcium concentrations typically found in the gut would strongly chelate IP6, precluding it from pre-emptively inducing toxin auto-proteolysis if administered exogenously. We therefore designed IP6 analogs with reduced susceptibility to complexation by calcium, which maintained allosteric activity at physiological calcium concentrations. We found that oral administration of IP6 analogs attenuated inflammation and promoted survival in mouse models of CDI. Our data provide impetus to further develop small-molecule allosteric triggers of toxin auto-proteolysis as a therapeutic strategy.
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