Clostridium difficile infection (CDI) is one of the most prolific causes of bacterial-induced diarrhea in the United States, with 3 million cases estimated annually. Newly emerged in its hypervirulent form, C. difficile also causes serious and potentially fatal inflammation of the colon. Because C. difficile is rapidly developing resistance to antibioti treatment, there is an urgent need to find an alternative therapy. Vancomycin and metronidazole remain treatment options for CDI, but neither is fully effective as is evident by the unacceptably high relapse rates. Two large enterotoxins (TcdA and TcdB) are the known causes of C. difficile-associated disease. Although an antitoxin vaccine program is currently in clinical trials, the efficacy of this approach remains highly uncertain since patients with severe CDI typically tend to be the elderly and the critically ill. Systemic antitoxin immunotherapy has recently been reported to be effective in preventing disease relapse in CDI patients, but fails to confer significant clinical benefits or reduce the length of hospitalization. Oral adaptation of passive antitoxin immunotherapy is currently not feasible or economical. Thus, there is an urgent need to develop new oral therapeutics for CDI. Our goal is to address these critical issues by performing highly innovative studies of the toxin virulence mechanism and by developing prototypic concepts for oral allosteric therapeutics that neutralize toxin activity in the colon. Tis work will be performed as a multi-institutional collaborative effort involving basic and clinical expertise of the C. difficile toxins, and in generating novel antitoxin therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI100914-03
Application #
8463992
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Ranallo, Ryan
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$369,655
Indirect Cost
$134,655
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Savidge, Tor C (2014) Importance of NO and its related compounds in enteric nervous system regulation of gut homeostasis and disease susceptibility. Curr Opin Pharmacol 19:54-60
Zhang, Yongrong; Shi, Lianfa; Li, Shan et al. (2013) A segment of 97 amino acids within the translocation domain of Clostridium difficile toxin B is essential for toxicity. PLoS One 8:e58634