Clostridium difficile (C. diff.) infection is estimated to cause nearly 0.5 million illnesses in the US. C. diff. can cause severe gastrointestinal effects, including life-threatening inflammation, is contagious, and is an urgent antibiotic-resistant threat, according to the Centers for Disease Control and Prevention. UCI researchers have determined the crystal structure for the virulent C. diff. toxin, TcdB, and characterized sites to target for neutralization along with immunogens that can be used in vaccine strategies to prevent and treat C. diff. infection.
·Treatment and prevention of Clostridium difficile infection
·Bead-based vaccination strategy
·Small, stable immunogens with native 3D structures against C. diff. toxins
·Low cost and non-toxic compared to current toxoids in clinical trials
Clostridium difficile-related diseases are the most common cause of antibiotic-associated diarrhea and gastroenteritis-associated death across developed countries. Primary treatment for C. diff. infection involves the use of antibiotics.In recent years, C. diff. stains have developed that are antibiotic resistant, contributing to the frequent occurrence of disease relapse which can increase hospital stays. As a result, C. diff. is classified as one of the top three urgent antibiotic resistance threats by CDC and more effective approaches to treatment and prevention are urgently needed.In the US alone, C. diff. infections affect more than 453,000 patients annually, resulting in 29,000 deaths and $6.3 billion in attributable costs.
C. diff. secrets two major toxins:TcdA and TcdB.Both modulate numerous physiological events in the cell and contribute directly to disease; however, TcdB is the more virulent of the two and is critical for inducing innate immune responses, most notably, inflammation, in the patient’s intestines.
UCI researchers have determined the first crystal structure of TcdB holotoxin, as well as multiple protein complexes that demonstrate mechanisms for neutralization.This data identifies novel drug targets and neutralizing epitopes against the virulent C. dif. toxin and have been utilized as such to develop multiple therapeutic antibodies.Immunogens engineered based on the structural data have the potential to be used as frontline therapeutics or in vaccine strategies for C. diff.
·Determined crystal structures of C. diff. toxin B
·Identification of multiple neutralizing epitopes on TcdB
·Completed preliminary vaccination studies in mice:sera show high titers against C. diff. toxin TcdB