title: Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination.
abstract: 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.
authors.affiliation: Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Stoltz
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Erickson
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Staley
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.|Department of Microbiology and Immunology, University of Minnesota , St. Paul, Minnesota 55108, United States.
authors.forename: Alexa R
authors.initials: AR
authors.lastname: Weingarden
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Romens
authors.affiliation: Departments of Medicine and Genetics, Cell Biology, and Development, University of Minnesota , VFW Cancer Research Center, 406 Harvard Street, Minneapolis, Minnesota, United States.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.|Department of Medicine, Division of Gastroenterology, University of Minnesota , Minneapolis, Minnesota 55414, United States.|Center for Immunology, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Khoruts
authors.affiliation: BioTechnology Institute, University of Minnesota , 1479 Gortner Avenue, St. Paul, Minnesota 55108, United States.|Department of Soil, Water & Climate, University of Minnesota , St. Paul, Minnesota 55108, United States.
authors.forename: Michael J
authors.identifier: 0000-0001-8779-2781
authors.initials: MJ
authors.lastname: Sadowsky
authors.affiliation: Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
authors.forename: Peter I
authors.identifier: 0000-0002-0081-3867
authors.initials: PI
authors.lastname: Dosa
mesh_terms: D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016360:Clostridioides difficile / Q000502:physiology*; D006801:Humans; D013171:Spores, Bacterial / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts