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Developing broad-spectrum therapeutics against C. difficile toxins

开发针对艰难梭菌毒素的广谱疗法

基本信息

批准号：
10348784
负责人：
Rongsheng Jin
金额：
$ 77.97万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-11 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348784
关键词：
Address Affinity Animal Model Animals Antibiotic Therapy Antibiotics Antibodies Antigens Binding Binding Sites Biology CSPG4 gene Cells Centers for Disease Control and Prevention (U.S.)Clinical Clostridium difficile Collaborations Colon Complex Cryoelectron Microscopy Developed Countries Disease Environment Epitopes Escape Mutant Extracellular Domain FDA approved Face Failure Family Formaldehyde Generations Goals Healthcare Human Immune response Immunize In Vitro Infection Knowledge Lead Mediating Membrane Molecular Monoclonal Antibodies Mus North America Passive Immunotherapy Pathogenesis Patients Phase Phase I/II Trial Prevention Protein Engineering Proteins Recovery Recurrence Relapse Reproduction spores Resistance Ribotypes Site Speed Structural Protein Structure Therapeutic Toxin Toxoids Vaccines Variant Virulence Factors alpha Toxin antibody mimetics antitoxin base clinical sequencing design gastrointestinal infection gut microbiota holotoxins in vivo infection risk neutralizing antibody neutralizing monoclonal antibodies neutralizing vaccine novel strategies novel vaccines opportunistic pathogen pathogenic bacteria patient population prevent prophylactic protein complex prototype rational design receptor receptor binding seal standard of care structural biology therapeutic development therapeutic protein therapeutically effective vaccine candidate vaccine development vaccine strategy

项目摘要

Project Summary Clostridioides difficile (C. difficile) is a major opportunistic pathogen that colonizes the colon when normal gut microbiota is disrupted. The large protein toxin TcdB is a major virulence factor responsible for diseases associated with C. difficile infection (CDI). However, prior efforts to develop neutralizing monoclonal antibodies and vaccines against TcdB have yielded unexpectedly low efficacy or even failure. We believe that a key weakness of these previous studies might be the complexity of toxin variations seen clinically. While a single toxin sequence from a reference strain has been widely used in all previous therapeutic development, sequencing TcdB in clinical isolates in recent years has revealed a growing number of C. difficile strains as well as variations in toxin sequences. This may account for the reduced neutralization efficacy of the only FDA- approved monoclonal antibody, bezlotoxumab, against some TcdB variants such as the one produced by a hypervirulent strain (ribotype 027). The sequence variation and the toxin’s large size (~270 kDa) also pose daunting challenges to develop effective vaccines using the traditional toxoid approach. Building on our recent progress in identification of toxin receptors and understanding the structure and function of TcdB, here we propose to develop receptor-decoy-based therapeutic proteins as broad-spectrum antitoxins and a new generation of epitope-focused fragment-based vaccines, which could provide effective protection against most of the known TcdB variants. Frizzled proteins (FZDs) and CSPG4 are two major host receptors for TcdB, and we previously have revealed the mechanism by which TcdB recognizes FZDs. The first aim in this project is to establish a structural understanding of TcdB binding to CSPG4. Our second aim will focus on design and characterization of a family of bi-specific receptor-decoy proteins, which are composed of the optimized TcdB- binding fragments of CSPG4 and FZDs. In the third aim, we will take advantage of our knowledge of the structures of TcdB holotoxin, TcdB–antibody complexes, and TcdB–receptor complexes to design candidate vaccines based on the selected highly conserved and functionally critical TcdB fragments. This project is built on long-standing productive collaborations between the Jin lab and the Dong lab, combining their highly complementary expertise in structural biology and protein engineering (Jin lab) and TcdB receptors/CDI pathogenesis/animal models (Dong lab). Successful completion of this project will provide prototypes of antitoxins for immunoprophylactic therapy and broad-spectrum candidate vaccines that offer prophylactic and long-lasting protection.

项目总结