Abstract：
: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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Ivarsson ME,Durantie E,Huberli C,Huwiler S,Hegde C,Friedman J,Altamura F,Lu J,Verdu EF,Bercik P,Logan SM,Chen W,Leroux JC,Castagner Bdoi
10.1016/j.chembiol.2018.10.002subject
Has Abstractpub_date
2019-01-17 00:00:00pages
17-26.e13issue
1eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30334-9journal_volume
26pub_type
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