High Throughput Screening for Non-antibiotic inhibitors of Clostridium difficile Pathophysiology

高通量筛选艰难梭菌病理生理学的非抗生素抑制剂

• 批准号: 10335182
• 负责人: Julian G Hurdle
• 金额: $ 50.26万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-11 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335182
• 关键词: Actins; Address; Adjuvant; Affect; Affinity; Aftercare; Anabolism; Anaerobic Bacteria; Animals; Antibiotics; Biological Assay; Biology; Biomass; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemistry; Clinical; Clostridium difficile; Collection; Communities; Critical Pathways; Data; Development; Diarrhea; Disease; Dose; Ensure; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidemic; Epithelial Cells; Functional disorder; Future; Genetic; Genomic approach; Glycyrrhetinic Acid; Goals; Growth; Growth Inhibitors; Health Sciences; Healthcare; Hospitals; Human; Image Analysis; In Vitro; Incidence; Individual; Infection; Institution; Intestinal Absorption; Isradipine; Kinetics; Knowledge; Lead; Libraries; Measures; Medical center; Medicine; Metabolic; Metabolic Pathway; Metronidazole; Microbiology; Modeling; Molecular; Monitor; Mus; Optics; Organism; Outcome Study; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacology; Phenotype; Pilot Projects; Production; Property; Public Health; Reading; Recurrence; Regulator Genes; Relapse; Reporter; Reproduction spores; Research; Research Support; Resistance; Resources; Ribotypes; Saint Jude Children' s Research Hospital; Severities; Stomach; Structure; Techniques; Technology; Testing; Texas; Therapeutic; Tissues; Toxin; Triage; Vancomycin; Variant; Virulence; Work; alpha Toxin; alternative treatment; antibiotic-associated diarrhea; antibody conjugate; antimicrobial; base; cellular targeting; cheminformatics; chemoproteomics; college; density; drug development; drug discovery; efficacy testing; gut microbiota; high throughput screening; in vivo; in vivo Model; inhibitor; lead optimization; logarithm; luminescence; metabolomics; microbiota; mutant; novel; patient prognosis; polymerization; prevent; promoter; recurrent infection; scaffold; screening; small molecule; standard of care; tool; trend

PROJECT SUMMARY/ABSTRACT Clostridium difficile is the main cause of antibiotic-associated diarrhea. Since 2003, the incidence and severity of C. difficile infection (CDI) has risen in the U.S. and globally. In the U.S. in 2011, there were ~29,000 deaths from ~500,000 CDI cases. In 2013 the CDC designated C. difficile as an Urgent Threat. These trends were related to the emergence of epidemic strains, in particular epidemic 027. Unfortunately, 20% or more of patients treated with the antibiotics metronidazole or vancomycin, undergoes a recurrence, which is a further frustrating feature of managing CDI, as the prognosis for patients with recurrent CDI is often poor. CDI recurrence partly results from damage of the intestinal microbiota community by metronidazole or vancomycin. There is a need for alternative treatments that are specific to disarming C. difficile without harming the gut microbiota. This is addressed in the proposed study, which seeks to develop a novel high-throughput screening (HTS) platform for discovering non-antibiotic compounds that specially inhibits C. difficile virulence, namely inhibiting cellular production of toxins that are responsible for tissue damage and spores that are responsible for recurrence. Preliminary data shows that such molecules do not harm the microbiota and reduce the onset of recurrent CDI in animals. The study proposes to establish a HTS platform for toxin synthesis inhibitors, which is feasible owing to state-of-the art facilities and resources at institutions involved in the study i.e. Texas A&M Health Science Center, St Jude Children’s Research Hospital, Baylor College of Medicine and supporting research cores in the Texas Medical Center. The team deploys a large compound collection for HTS, automated and semi-automated screening technologies, and novel in vitro and in vivo microbiota models that are clinically reflective of CDI. The studies outcome will be one or more candidate scaffolds that are suitable for lead optimization and drug development. These molecules will help to probe ill-defined molecular pathogenic mechanisms to understand the biology of this organism. Public health. The successful completion of this study impacts healthcare by advancing candidate molecules for drug development to save lives by reducing the onset of CDI.

项目总结/摘要 艰难梭菌是腹泻的主要原因。自2003年以来， 梭艰难梭菌感染（CDI）在美国和全球范围内有所上升。在美国，2011年有约29，000人死亡 约50万例CDI病例。2013年，CDC将C.这是一个紧迫的威胁。这些趋势 与流行菌株的出现有关，特别是流行027。不幸的是，20%或更多的患者 用抗生素甲硝唑或万古霉素治疗，复发，这是一个进一步令人沮丧的 这是管理CDI的一个特点，因为复发性CDI患者的预后往往很差。CDI部分复发 由甲硝唑或万古霉素对肠道微生物群的损害引起。有必要 寻找替代疗法来解除C的武装而不伤害肠道微生物群。这是 该研究旨在开发一种新的高通量筛选（HTS）平台， 发现非抗生素化合物，特别是抑制C。艰难梭菌毒力，即抑制细胞 毒素的产生是造成组织损伤的原因，孢子是造成复发的原因。 初步数据显示，这些分子不会损害微生物群，并减少复发性CDI的发生。 在动物身上。本研究提出建立一个毒素合成抑制剂的HTS平台，这是可行的， 参与研究的机构（即德克萨斯A&M健康科学）的最先进设施和资源 中心，圣裘德儿童研究医院，贝勒医学院和支持研究核心， 德州医疗中心该团队为HTS部署了一个大型的自动化和半自动化化合物集合 筛选技术，以及临床上反映CDI的新型体外和体内微生物群模型。的 研究结果将是一个或多个候选支架，适用于铅优化和药物 发展这些分子将有助于探索不明确的分子致病机制， 这种生物体的生物学。公共卫生本研究的成功完成通过以下方式对医疗保健产生影响 推进药物开发的候选分子，通过减少CDI的发作来挽救生命。