Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination

Kristen L. Stoltz, Raymond Erickson, Christopher Staley, Alexa R. Weingarden, Erin Romens, Clifford J. Steer, Alexander Khoruts, Michael J. Sadowsky, Peter I. Dosa

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36 Scopus citations


Standard antibiotic-based strategies for the treatment of Clostridium difficile infections disrupt indigenous microbiota and commonly fail to eradicate bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were well-tolerated and several tetrazole-containing derivatives were highly potent inhibitors in both assays, with complete inhibition of spore germination observed at 10-25 μM. To limit intestinal absorption, C7-sulfated analogues designed to avoid active and passive transport pathways were prepared. One of these derivatives, compound 21b, was found to be a potent inhibitor of C. difficile spore germination and poorly permeable in a Caco-2 model of intestinal epithelial absorption, suggesting that it is likely to be gut-restricted.

Original languageEnglish (US)
Pages (from-to)3451-3471
Number of pages21
JournalJournal of medicinal chemistry
Issue number8
StatePublished - Apr 27 2017

Bibliographical note

Funding Information:
Research reported in this publication was supported by Faculty Research Development Grant 14.30 from the University of Minnesota Academic Health Center (A.K., P.I.D., M.J.S.) and by NIH grant 1R21-AI114722-01 (M.J.S. and A.K.). Caco-2 assays were performed by Eurofins Panlabs.

Publisher Copyright:
© 2017 American Chemical Society.


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