Tailoring Novel Therapeutics for Emerging Drug-Resistant C. Difficile Colitis

为新兴耐药艰难梭菌结肠炎定制新疗法

基本信息

批准号：
7325378
负责人：
RICHARD L GUERRANT
金额：
$ 69.78万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7325378
关键词：
10 year old Actins Address Adenosine Adenosine A2A Receptor Adenosine A2B Receptor Affect Age Agonist Amino Acids Animal Model Animals Anti-Inflammatory Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Apoptosis Apoptotic Bacterial Toxins Basic Science Biological Biological Availability Biological Models Biology Bone Marrow Bone Marrow Transplantation C57BL/6 Mouse Canada Cell Death Cell Wall Cell model Cell physiology Cells Cessation of life Child Chimera organism Ciprofloxacin Clindamycin Clinical Clinical Trials Clostridium difficile Colectomy Colitis Collection Communities Cytoskeleton Cytotoxin Data Development, Other Diarrhea Disease Disruption Drug Delivery Systems Drug Kinetics Drug resistance Elderly Enteral Epithelial Epithelial Cells Epithelium Frequencies Generations Genes Genetic Goals Grant Hamsters Healed Healthcare Histologic Home environment Hospitals Human In Vitro Individual Infection Inflammation Inflammatory Injury Intellectual Property Intervention Intestinal Secretions Intestines Knock-out Knockout Mice Knowledge Laboratories Lead Libraries Life Ligands Lymphocyte Mediating Mesocricetus auratus Metronidazole Modeling Mus Numbers Nurses Opportunistic Infections Oral Organism Organoids Oryctolagus cuniculus Outcome Pathogenesis Pathology Pathway interactions Patients Peptides Peptidoglycan Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Pharyngitis Phase Philadelphia Predisposition Pregnancy Principal Investigator Prodrugs Production Publishing Purinergic P1 Receptors Quebec Quinolones Rate Relapse Relative (related person)Research Risk Role Severities Severity of illness Signal Pathway Signal Transduction Site Speed Standards of Weights and Measures Symptoms System Testing Text Therapeutic Tilia Toll-Like Receptor 2 Toxic Megacolon Toxic effect Toxin Twin Multiple Birth Universities University Hospitals Vancomycin Vancomycin resistant enterococcus Variant Virginia Virulence Factors Visit Water Whole Organism Woman Work absorption alanylglutamine cellular targeting combinatorial concept cytokine cytotoxic design drug development experience fluoroquinolone resistance gastrointestinal girls granulocyte healing human disease improved in vivo in vivo Model injury and repair innovation leukocyte activation macrophage mast cell mortality neutralizing antibody neutrophil novel novel strategies novel therapeutics older women pathogen prevent quinolone resistance receptor repaired response rho sugar tissue culture

项目摘要

DESCRIPTION (provided by applicant): Until recently, C. difficile associated diarrhea (CDAD) occurred as an opportunistic infection in older hospitalized patients on antibiotics. Currently, CDAD has become much more worrisome because of widespread increases in its frequency and severity throughout the US and Canada due to the emergence of hypertoxinogenic, binary toxin-producing, quinolone-resistant (Bl) strains. Furthermore, life threatening CDAD is now affecting healthy younger people in communities, even without recent antibiotic use. Even worse, current treatment consisting of more antibiotics is failing and often prolongs shedding or relapses. Hence we urgently need novel approaches that block toxin-induced colitis to prevent the progression of colitis produced by C. difficile toxin(s)) without further disruption of protective flora. This application from the University of Virginia brings together our experienced enterics laboratory team with basic science colleagues in toxin pathogenesis and in drug development, and a pharmaceutical partner (Adenosine Therapeutics, LLC). We shall address the emerging quinolone-resistant C. difficile colitis with an innovative antitoxic approach that is supported by pilot data demonstrating considerable promise. We propose to investigate three types of anti-inflammatory agents alone and in combination: adenosine A2A receptor agonists that block leukocyte activation; A2B antagonists that block cytokine production by epithelial and mast cells, and the pro-absorptive injury repairing agent, alanyl-glutamine. The first three closely interrelated specific aims are designed to determine how these novel therapeutics regulate intestinal cell targets to block toxin-induced apoptosis, inflammation, and secretion. We plan to: 1) use new human intestinal epithelial cell organoid and C57BL/6 murine models to define the targets of purified toxins A and B as well as B-variant and new Bl strain supernatants; 2) use C57BL/6 mice with adenosine receptor knockouts and Cre/loxp targeted cellular AaA receptor deletions to define the relevant adenosine targets to inhibition of toxin effects; and 3) use the information gained in aims 1 and 2 to test combinations of A2A agonists, A2B antagonists and alanyl-glutamine, alone and in combination, in animal models in order to prepare for clinical trials of these novel drug therapies for increasingly serious CDAD in humans. Our fourth aim involves discovery efforts towards developing more highly absorbed AaR agonists and the synthesis of the proposed A2A, agonists and A2B antagonists necessary to support this grant.

描述（由申请人提供）：直到最近，艰难梭菌相关性腹泻（CDAD）作为一种机会性感染出现在接受抗生素治疗的老年住院患者中。目前，由于高产毒、二元毒素、喹诺酮耐药 (Bl) 菌株的出现，CDAD 在美国和加拿大的发病率和严重程度普遍增加，因此变得更加令人担忧。此外，危及生命的 CDAD 现在正在影响社区中健康的年轻人，即使最近没有使用抗生素。更糟糕的是，目前由更多抗生素组成的治疗失败了，并且常常会延长脱落或复发的时间。因此，我们迫切需要阻断毒素诱导的结肠炎的新方法，以防止艰难梭菌毒素产生的结肠炎的进展，而不进一步破坏保护性菌群。弗吉尼亚大学的这一应用程序汇集了我们经验丰富的肠溶实验室团队、毒素发病机制和药物开发方面的基础科学同事以及制药合作伙伴 (Adenosine Therapeutics, LLC)。我们将采用创新的抗毒方法来解决新出现的喹诺酮耐药性艰难梭菌结肠炎，该方法得到了试验数据的支持，显示出巨大的前景。我们建议单独或联合研究三种类型的抗炎药：阻止白细胞活化的腺苷 A2A 受体激动剂； A2B 拮抗剂可阻断上皮细胞和肥大细胞产生细胞因子，以及促吸收性损伤修复剂丙氨酰谷氨酰胺。前三个密切相关的具体目标旨在确定这些新疗法如何调节肠道细胞靶点以阻止毒素诱导的细胞凋亡、炎症和分泌。我们计划：1）使用新的人肠上皮细胞类器官和C57BL/6小鼠模型来定义纯化毒素A和B以及B变体和新Bl菌株上清液的靶标； 2) 使用腺苷受体敲除和 Cre/loxp 靶向细胞 AaA 受体缺失的 C57BL/6 小鼠来定义抑制毒素作用的相关腺苷靶点； 3) 使用目标 1 和 2 中获得的信息在动物模型中测试 A2A 激动剂、A2B 拮抗剂和丙氨酰谷氨酰胺的组合（单独或组合），以便为这些新型药物疗法治疗日益严重的 CDAD 的临床试验做好准备在人类中。我们的第四个目标涉及发现工作，以开发吸收性更高的 AaR 激动剂，以及支持此项资助所需的拟议 A2A、激动剂和 A2B 拮抗剂的合成。