Clostridioides difficile infection (CDI) is an anaerobic bacterium that is responsible for most antibiotic-associated cases of diarrhea. CDI begins with the ingestion of an environmentally stable spore that germinates within the GI tract under specific conditions. We have shown that the bile salt analog N-phenyl-cholan-24-amide (1) can inhibit spore germination and prevent CDI in animal models of infection. Unfortunately, 1, was stable in the gut of antibiotic-treated animals but was rapidly degraded by gastrointestinal micoflora in the normal gut preventing its use to prevent CDI. We hypothesized that the source of the instability was the amide group. To explore this hypothesis, we removed the amide by either converting it to an amine or to 5,6-fused heterocycles. We found that reduction of the amide to an amine resulted in a significant loss of activity, but conversion to benzimidazole (6a), benzothiazole (6b), or benzoxazole (6c) gave compounds with good antigermination activity. Exploration of other sterane groups such as chenodeoxycholate and deoxycholate gave active compounds only for the benzimidazole series. Examination of 6b showed that it was stable for 24 hours in the presence of feces taken from healthy mice validating the hypothesis that an amide bioisostere would increase the stability of the compound. Mice treated with 6a and 6b also showed no signs of toxicity up to 300 mg/kg daily for 7 days. Each compound was tested for its ability to prevent CDI in a murine model. Compound 6b but not 6a was able to prevent CDI when given at a dose of 50 mg/kg.