A host-targeted small-molecule that inhibits entry of Clostridium difficile toxins and reduces disease pathogenesis in mice

Clostridium difficile is the leading cause of nosocomial diarrhea and colitis in the industrialized world. Infections are triggered, paradoxically, by antibiotics, which disrupt the protective gut microbiota, allowing antibiotic-resistant C. difficile to flourish. Once colonized, pathogenic C. difficile secrete up to three different protein toxins, which are directly responsible for the devastating gastrointestinal sequelae. Targeting toxin action is therefore an appealing therapeutic strategy to treat C. difficile infection. Here, we show that niclosamide, an FDA-approved anthelmintic drug, inhibits the pathogenesis of all three toxins by targeting a host process required for entry by each toxin. In a spore-challenge model we show that niclosamide protects mice from infection by a hypervirulent strain of C. difficile expressing all three toxins, without disrupting the composition of the protective gut microbiota. Niclosamide may fill an important unmet clinical need for an oral agent to treat primary C. difficile infection.