Argyrin B exhibits potent therapeutic efficacy in a Clostridioides difficile-infection mouse model while preserving microbiota functionality.

Clostridioides difficile infection (CDI) remains a leading cause of antibiotic-associated diarrhoea, with high recurrence rates and limited treatment options that preserve gut microbiota. Current treatments, including vancomycin, further disrupt the already compromised gut microbiota, often prolonging dysbiosis and increasing the risk of colonization by resistant pathogens. This study demonstrates that argyrin B exhibits potent activity against C. difficile in vitro and significantly reduces bacterial burden in a mouse model of infection. Argyrin B displayed a narrow antimicrobial spectrum, suggesting that commensal gut bacteria are hardly affected, and may allow for a faster restoration of the antibiotic pre-damaged gut microbiota. The compound exhibited a pharmacokinetic profile characterized by low systemic absorption and elevated colonic concentrations, representing favourable characteristics. The compound acts through a novel mechanism by targeting elongation factor G, distinct from existing therapies, and resistance emerged at low frequency via point mutations in the target gene. These features suggest that argyrin B may offer a novel and well-tolerated therapeutic approach for CDI, with potential to support microbiota preservation, which may contribute to reduced recurrence risk.