BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of antibiotic-associated diarrhea. The infective form of C. difficile is the spore, but the vegetative bacterium causes the disease. Because C. difficile spore germination is required for symptomatic infection, antigermination approaches could lead to the prevention of CDI. We recently reported that CamSA, a bile salt analog, inhibits C. difficile spore germination in vitro. METHODS: Mice infected with massive inocula of C. difficile spores were treated with different concentrations of CamSA and monitored for CDI signs. C. difficile spore and vegetative cells were counted in feces from infected mice. RESULTS: A single 50-mg/kg dose of CamSA prevented CDI in mice without any observable toxicity. Lower CamSA doses resulted in delayed CDI onset and less severe signs of disease. Ingested C. difficile spores were quantitatively recovered from feces of CamSA-protected mice. CONCLUSIONS: Our results support a mechanism whereby the antigermination effect of CamSA is responsible for preventing CDI signs. This approach represents a new paradigm in CDI treatment. Instead of further compromising the microbiota of CDI patients with strong antibiotics, antigermination therapy could serve as a microbiota surrogate to curtail C. difficile colonization of antibiotic-treated patients.
BACKGROUND:Clostridium difficileinfection (CDI) is a leading cause of antibiotic-associated diarrhea. The infective form of C. difficile is the spore, but the vegetative bacterium causes the disease. Because C. difficile spore germination is required for symptomatic infection, antigermination approaches could lead to the prevention of CDI. We recently reported that CamSA, a bile salt analog, inhibits C. difficile spore germination in vitro. METHODS:Mice infected with massive inocula of C. difficile spores were treated with different concentrations of CamSA and monitored for CDI signs. C. difficile spore and vegetative cells were counted in feces from infected mice. RESULTS: A single 50-mg/kg dose of CamSA prevented CDI in mice without any observable toxicity. Lower CamSA doses resulted in delayed CDI onset and less severe signs of disease. Ingested C. difficile spores were quantitatively recovered from feces of CamSA-protected mice. CONCLUSIONS: Our results support a mechanism whereby the antigermination effect of CamSA is responsible for preventing CDI signs. This approach represents a new paradigm in CDI treatment. Instead of further compromising the microbiota of CDI patients with strong antibiotics, antigermination therapy could serve as a microbiota surrogate to curtail C. difficile colonization of antibiotic-treated patients.
Authors: Kristen L Stoltz; Raymond Erickson; Christopher Staley; Alexa R Weingarden; Erin Romens; Clifford J Steer; Alexander Khoruts; Michael J Sadowsky; Peter I Dosa Journal: J Med Chem Date: 2017-04-12 Impact factor: 7.446