Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection.

Spore-forming bacteria encompass a diverse range of genera and species， including important human and animal pathogens， and food contaminants. Clostridioides difficile is one such bacterium and is a global health threat because it is the leading cause of antibiotic-associated diarrhoea in hospitals. A crucial mediator of C. difficile disease initiation， dissemination and re-infection is the formation of spores that are resistant to current therapeutics， which do not target sporulation. Here， we show that cephamycin antibiotics inhibit C. difficile sporulation by targeting spore-specific penicillin-binding proteins. Using a mouse disease model， we show that combined treatment with the current standard-of-care antibiotic， vancomycin， and a cephamycin prevents disease recurrence. Cephamycins were found to have broad applicability as an anti-sporulation strategy， as they inhibited sporulation in other spore-forming pathogens， including the food contaminant Bacillus cereus. This study could directly and immediately affect treatment of C. difficile infection and advance drug development to control other important spore-forming bacteria that are problematic in the food industry (B. cereus)， are potential bioterrorism agents (Bacillus anthracis) and cause other animal and human infections.