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Clostridium difficile

Clostridium difficile infections (CDI) are a major public health concern, with the number of cases doubling from 2002 to 2006 to 500,000 infections per year in the United States. The resulting costs for treatment are greater than $1 billion annually.  CDI are becoming increasingly prevalent in hospitals, long-term and primary-care facilities, primarily in patients whose normal intestinal flora have been compromised by antibiotic treatment. CDI are debilitating and lead to 14,000 deaths annually in the US. Moreover, in recent years, an epidemic strain of C. difficile, B1/NAP1/O27, has emerged with an associated mortality rate of up to 30%. In addition, severe, complicated cases are often treatment-refractory. Current treatment with broad-spectrum antimicrobial therapy is generally effective, but pre-disposes 30% of patients to recurrence due to continued disruption of normal gut flora.

CDI primary virulence mechanism is the production of two toxins, TcdA and TcdB, which glucosylate Rho-family GTPases, disrupt the actin cytoskeleton, and causing cytotoxicity and inflammation. These toxins are essential for virulence, as strains that lack them do not cause disease. Our approach is to identify non-antibiotic inhibitors of C. difficile toxin, which is responsible for the symptoms associated with CDI, while preserving healthy gut microbiome. As such, we developed a two-pronged approach by conducting a phenotypic screen for toxin synthesis inhibitors and a mechanistic screen for direct inhibitors of TcdB.

Antibiotic treatment leads to C. difficile.

From these screens, we identified multiple classes of small molecule inhibitors that reduce C. difficile toxin synthesis, or block TcdB/TcdA activity. The latter class of compounds inhibits TcdB activity from several C. difficile strains including from the epidemic B1/NAP1/O27 strain. There is no apparent toxicity towards a variety of gut flora bacterial species or to human cells in culture.  We are currently testing multiple series of chemical compounds in in vivo mouse and hamster models.