An aniline-substituted bile salt analog protects both mice and hamsters from multiple Clostridioides difficile strains
Overview
Clostridioides difficile (formerly Clostridium difficile) is a pathogenic bacterium responsible for the majority of nosocomial antibiotic-associated diarrhea. Collectively, disease caused by this bacterium is recognized as Clostridioides difficile infection (CDI). The emergence of hypervirulent C. difficile strains has led to increases in both hospital- and community-acquired CDI. Furthermore, CDI relapse from hypervirulent strains can reach up to 25%. Thus, standard treatments are rendered less effective, making new methods of prevention and treatment more critical. Previously, the bile salt analog CamSA was shown to inhibit spore germination in vitro and protect mice and hamsters from C. difficile strain 630. Here, we show that CamSA was less active at preventing spore germination of other C. difficile ribotypes, including the hypervirulent strain R20291. Strain-specific in vitro germination activity of CamSA correlated with its ability to prevent CDI in mice. Additional bile salt analogs were screened for germination inhibition activity against strain R20291, and the most active compounds were tested against other C. difficile strains. An aniline-substituted bile salt analog, (CaPA), was found to be a better anti-germinant in vitro than CamSA in seven different C. difficile strains. In addition, CaPA was capable of reducing, delaying, or preventing CDI signs in mice infected with diverse C. difficile strains, with minor but significant effects on the gut microbiome. CaPA’s efficacy was further confirmed by its ability to prevent CDI in strain 630-infected hamsters. These data suggest that C. difficile spores respond to germination inhibitors in a strain-dependent manner. However, careful screening can identify anti-germinants with broad CDI prophylaxis activity.
Files containing the original unfiltered sequences are available from the NCBI under BioProject number PRJNA749826 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA749826)
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- data/ # raw data generated using QIIME2
- code/ # R scripts