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.

Public Health Relevance

This work will use mechanistic approaches for the rational design and synthesis of novel allosteric therapeutics for Clostridium difficile infection, which causes widespread intestinal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI100914-01
Application #
8343416
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Ranallo, Ryan
Project Start
2012-06-01
Project End
2012-08-31
Budget Start
2012-06-01
Budget End
2012-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$107,725
Indirect Cost
$37,317
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Chen, Deliang; Oezguen, Numan; Urvil, Petri et al. (2016) Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv 2:e1501240
Ross, Caná L; Spinler, Jennifer K; Savidge, Tor C (2016) Structural and functional changes within the gut microbiota and susceptibility to Clostridium difficile infection. Anaerobe 41:37-43
Spinler, Jennifer K; Ross, Caná L; Savidge, Tor C (2016) Probiotics as adjunctive therapy for preventing Clostridium difficile infection - What are we waiting for? Anaerobe 41:51-57
Luna, Ruth Ann; Savidge, Tor C; Williams, Kent C (2016) The Brain-Gut-Microbiome Axis: What Role Does It Play in Autism Spectrum Disorder? Curr Dev Disord Rep 3:75-81
Spinler, Jennifer K; Brown, Aaron; Ross, Caná L et al. (2016) Administration of probiotic kefir to mice with Clostridium difficile infection exacerbates disease. Anaerobe 40:54-7
MacEachern, Sarah J; Patel, Bhavik A; Keenan, Catherine M et al. (2015) Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis. Gastroenterology 149:445-55.e3
Savidge, Tor C (2015) Epigenetic Regulation of Enteric Neurotransmission by Gut Bacteria. Front Cell Neurosci 9:503
Yu, Hua; Chen, Kevin; Wu, Jianguo et al. (2015) Identification of toxemia in patients with Clostridium difficile infection. PLoS One 10:e0124235
Chen, Deliang; Savidge, Tor (2015) BIOPHYSICS. Comment on ""Extreme electric fields power catalysis in the active site of ketosteroid isomerase"". Science 349:936
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

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