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UCI-led study suggests new molecular target for therapeutic interventions aimed at C. difficile infection

Cdiff
UCI School of Medicine
The VPI10463 and M68 represent the classic and the hypervirulent C. difficile, respectively. GTD-VPI preferentially modifies Rho family GTPases (Cdc42, for example) by glucosylation, while GTD-M68 more effectively modifies R-Ras. Due to their different selectivity toward Rho or Ras family GTPases, these two different TcdB variants cause two distinct types of cytopathic effects.

Findings show structural basis for TcdB recognition of small GTPases Rho and R-Ras

Irvine, Calif., Oct. 22, 2021 — A University of California, Irvine-led study suggests that the glucosyltransferase domain (GTD) is an ideal molecular target for therapeutic interventions for Clostridioides difficile infection (CDI). These findings may lead to new treatments to fight this deadly disease.

Based on their findings that established the structural basis for Toxin B recognition of the small GTPases Rho and R-Ras families, the study, titled “Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B,” was published today in Science Advances.

CDI is the leading cause of antibiotic-associated diarrhea and gastroenteritis-associated deaths worldwide, accounting for 500,000 cases and 29,000 deaths annually in the U.S. Classified by the Centers for Disease Control and Prevention as one of the top health threats. There is growing global concern surrounding the emerge and spread of hypervirulent C. difficile strains, resembling the occurrence of new virus variants in current COVID pandemic. TcdB is one of two homologous C. difficile exotoxins, and TcdB alone is capable of causing the full spectrum of CDI diseases.

“We focused on the structure and function of TcdB’s crucial GTD, which is the toxin’s ‘warhead.’ The GTD is delivered by the toxin inside the host cells and causes most of the cytosolic damage to patients,” said Rongsheng Jin, PhD, professor in the Department of Physiology & Biophysics at the UCI School of Medicine, and corresponding author. “We discovered molecular mechanisms by which the GTD specifically recognizes and blocks the physiological functions of the human GTPases Rho and R-Ras enzyme families that are crucial signaling molecules.”

The team also demonstrated how the classic form of TcdB and the hypervirulent TcdB recognize their human targets in different ways, which leads to distinct structural changes to the host cells caused by bacterial invasion.

“Once the GTD of TcdB is inside the cells, it is shielded by our cells and becomes inaccessible to passive immunotherapy. But our studies suggest that small molecule inhibitors could be developed to disarm the GTD, which will directly eliminate the root cause of disease symptoms and cellular damage,” Jin said. “This new strategy can potentially be integrated with and complement other CDI treatment regiments.”

This work was supported by the National Institutes of Health under awards R01AI125704, R21AI139690, R21AI123920, R01NS080833, R01AI132387, R01AI139087 and R21 CA235533.

Team members also include Zheng Liu and Peng Chen from the UCI Department of Physiology & Biophysics; Sical Chang, Songhai Tian, Ji Zeng, and Min Dong, Department of Urology, Boston Children’s Hospital, and Department of Microbiology and Surgery, Harvard Medical School, Boston; and Kay Perry, NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York; and Argonne National Laboratory, Lemont, Illinois.

About the UCI School of Medicine: Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.

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