Irvine, CA – June 18, 2021 – A new study paves the way for the development of next generation therapeutics for the prevention and treatment of Clostridioides difficile Infection (CDI), the leading cause of healthcare acquired gastrointestinal infections and deaths in developed countries.
Published today in Nature communication, the study shows the first 3D structure of the of Clostridioides difficile Toxin B (TcdB) in complex with chondroitin sulfate proteoglycan 4 (CSPG4), a human receptor. The study was co-led by senior author Rongsheng Jin, PhD, professor in the Department of Physiology & Biophysics at the University of California, Irvine, School of Medicine, and Min Dong, PhD, associate professor at Harvard Medical School.
“TcdB is one of two homologues C. difficult Exotoxins, which are the main virulence factors responsible for the spread of C. difficult Infections, ”said Jin. “TcdB alone is able to cause the full spectrum of CDI-associated diseases in humans.”
Previous studies had identified CSPG4 as a potential receptor for TcdB, but the pathophysiological relevance and molecular details were unknown. The results of this new study reveal a unique binding site involving TcdB and CSPG4, and also show that CSPG4 binding residues are highly conserved in most of the TcdB variants known to date.
CDI is the leading cause of antibiotic-associated diarrhea and gastroenteritis-associated deaths in developed countries, causing approximately 223,900 infections, 12,800 deaths, and $ 1 billion in healthcare costs in the United States in 2017. Top five “pressing threats” by CDC. In addition, there is growing concern around the world about the emergence of rapidly spreading hypervirulants C. difficult Burdens reminiscent of the current COVID pandemic.
“These new findings tell us that a rationally designed CSPG4-mimicking bait could neutralize the major TcdB variants and offer a unique therapeutic avenue to combat some of the hypervirulants C. difficult Burdens, ”said Jin. In contrast, the researchers also showed that the therapeutic mechanism of bezlotoxumab, the only FDA-approved anti-TcdB antibody, is sensitive to escaping mutations in some strains of bacteria.
The current standard of care for CDI includes broad spectrum antibiotic treatments, which often lead to frequent recurrences of the disease. While bezlotoxumab may reduce the recurrence rate of CDI in some patients, the results of this and some previous studies suggest that it may be less effective than some TcdB variants.
“We designed a CSPG4-mimicking bait based on the 3D structure we observed that could neutralize the major TcdB variants and, in our studies, is superior to bezlotoxumab for a major TcdB variant of a hypervirulent strain (TcdB2). As a highly conserved cellular receptor of TcdB, it would be difficult for TcdB to escape a CSPG4 bait molecule because any mutations that disrupt toxin binding to the bait would also disrupt binding to its native receptors, “Jin said.
Based on these new findings, as well as an earlier discovery of how TcdB recognizes another human Frizzled (FZD) receptor, the research team has also developed a family of recombinant protein therapeutics.
“We are now investigating the therapeutic properties of these novel antitoxin molecules and believe that they offer broad spectrum protection and neutralization against most known TcdB variants and thus could improve existing antibody therapeutics for CDI,” said Jin, whose team has pending a patent on these neutralizing molecules.
This work was supported in part by the National Institutes of Health, the Lower Saxony Vorab, the German Research Foundation, and the Burroughs Wellcome Fund.
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