A small-molecule antivirulence agent for treating Clostridium difficile infection

Kristina Oresic Bender, Megan Garland, Jessica A. Ferreyra, Andrew J. Hryckowian, Matthew A. Child, Aaron W. Puri, David E. Solow-Cordero, 

Steven K. Higginbottom, Ehud Segal, Niaz Banaei, Aimee Shen, Justin L. Sonnenburg, Matthew Bogyo.

Science translational medicine. 2015 Sep 23;7(306):306ra148.

Speaker: Shiau-Ting Yang (楊曉婷)                             Time: 13:00~14:00, Sep. 21, 2016

Commentator: Dr. Ching-Hao Teng (鄧景浩教授)  Place: Room 601

Abstract:

Clostridium difficile (C. difficile) is a gram-positive, spore-forming anaerobic bacillus and a cause of emerging global health concern in both hospital and community settings. Clostridium difficile infection (CDI) is commonly triggered by using broad spectrum antibiotics which disrupt the normal gut microbiota and exposure to C. difficile spores. The annual increasing cases and severity of CDI with the high mortality, high recurrence rate, high medical burden and emergence of multiple antibiotic-resistant strains have result in an urgent need for new treatments (1). In this article, the authors developed a fluorescence polarization high-throughput screen (HTS) to target the cysteine protease domain (CPD) of the C. difficile major virulence factor toxin B (TcdB) (2). The authors identified a library of bioavailable drugs after a targeted screen for this protease domain to discover a compound, ebselen, which is currently undergoing clinical trials for the prevention and treatment of various disorders and is known to be clinically safe with a well-known pharmacology profile. Ebselen presented inhibitory effect against both major toxin TcdA and TcdB in biochemical and cell rounding assays. In addition, the authors further investigate the treatment of ebselen in CDI mouse infection model to confirm its therapeutic effectiveness. They found that ebselen can reduce the colonic tissue symptoms of disease that related directly with inhibition of the release of the toxic glucosyltransferase domain (GTD). In short, the authors demonstrated that the new non-antibiotic drug has a high potential to be developed as a novel

therapeutic agent for CDI treatment.

References:

1.     Dubberke ER, Olsen MA. (2012) Burden of Clostridium difficile on the healthcare system. Clinical infectious diseases : an official publication of the Infectious Diseasea Society of America. 2:S88-92.

2.     Pruitt RN, Lacy DB. (2012) Toward a structural understanding of Clostridium difficile toxins A and B. Frontiers in cellular and infection microbiology. 16;2:28.