C. difficile (or C. diff) is an antibiotic-resistant ‘superbug’ that causes life-threating diarrhea. Recently the US Centers for Disease Control and Prevention (CDC) listed C. diff as the top ‘Urgent Antibiotic Resistant Threats’. Infections almost always occur in people that have recently taken antibiotics, which wipe out the healthy gut bacteria, allowing resistant C. diff to thrive. C. diff causes disease by secreting an armada of toxins that enter and destroy the cells of the colon leading to symptoms ranging from mild diarrhea to life-threatening toxic megacolon. Therapies that prevent the symptoms of disease without disrupting the healthy gut bacteria are urgently needed.
In a new study that was published in Nature Communications, a team led by Roman Melnyk, Associate Professor in the Department of Biochemistry at the University of Toronto and Senior Scientist in the Molecular Medicine program at SickKids, screened thousands of small-molecule drugs to find any that might block the effects of the deadly toxins – without affecting the gut bacteria. Niclosamide, a drug that was approved decades ago for treating tapeworm infections, emerged as a promising candidate given its excellent safety profile in humans and its proclivity for accumulating in the gut, where the toxins of C. diff act. They found that Niclosamide protected human colon cells in a dish from all of the C. diff toxins by preventing their uptake into cells. With collaborators at the University of Maryland, they went on to show that Niclosamide prevented disease in mice infected with a hypervirulent strain of C .diff. Further, they showed that Niclosamide did not disrupt the healthy bacteria in the gut. In today’s climate of sky-high drug prices, repurposing old drugs for new diseases is one way of getting new treatments into the clinic faster and at a reduced cost. If ongoing efforts to get niclosamide into the clinic are successful, niclosamide could become a prototype for non-antibiotic drugs against infectious diseases.
John Tam, Therwa Hamza, Bing Ma, Kevin, Chen, Greg L. Beilhartz, Jacques Ravel, Hanping Feng, & Roman A. Melnyk “Host-targeted niclosamide inhibitors C. difficile virulence and prevents disease in mice without disrupting the gut microbiota” Nature Communications (2018) <DOI: 10.1038/s41467-018-07705-w>
