Small-Molecule Allosteric Triggers of Clostridium difficile Toxin B Auto-proteolysis as a Therapeutic Strategy.

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 Biol

journal_title

Cell chemical biology

authors

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 B

doi

10.1016/j.chembiol.2018.10.002

subject

Has Abstract

pub_date

2019-01-17 00:00:00

pages

17-26.e13

issue

1

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(18)30334-9

journal_volume

26

pub_type

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