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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要/摘要艰难梭菌是抗生素相关腹泻的主要原因。自2003年以来，事件和严重性艰难梭菌感染（CDI）在美国和全球上升。在2011年的美国，有约29,000人死亡来自约500,000个CDI案件。 2013年，CDC将艰难梭菌视为紧急威胁。这些趋势是与流行病的出现有关，特别是流行病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，经历了复发，这是进一步令人沮丧的管理CDI的特征，因为复发性CDI患者的预后通常很差。 CDI复发部分甲硝唑或万古霉素对肠道菌群群落的损害产生。有需要对于特定于解除艰难梭菌而不损害肠道菌群的替代治疗方法。这是在拟议的研究中解决，该研究旨在开发一种新型的高通量筛选（HTS）平台发现非抗生素化合物特殊抑制艰难梭菌病毒，即抑制细胞产生负责组织损伤的毒素和负责复发的孢子。初步数据表明，这种分子不会损害微生物群，并减少经常性CDI的发作在动物中。研究提案建立了HTS合成抑制剂的HTS平台，这是可行的到研究的机构的最先进的设施和资源，即德克萨斯州A＆M健康科学中心，圣裘德儿童研究医院，贝勒医学院和支持研究核心德克萨斯医疗中心。该团队为HTS，自动化和半自动部署了一个大型化合物系列筛选技术以及在临床上反映CDI的体外和体内微生物群模型。这研究结果将是适合铅优化和药物的一个或多个候选支架发展。这些分子将有助于探测未定义的分子致病机制以理解这种生物的生物学。公共卫生。这项研究的成功完成影响了医疗保健通过减少CDI的发作来推动候选分子进行药物开发以挽救生命。