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

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.