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：
8113277
负责人：
RICHARD L GUERRANT
金额：
$ 72万
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113277
关键词：
Address Adenosine Adenosine A2A Receptor Adenosine A2B Receptor Affect Agonist Amino Acids Animal Model Animals Anti-Inflammatory Agents Antibiotics Apoptosis Apoptotic Bacterial Toxins Basic Science Biological Availability Bone Marrow Transplantation C57BL/6 Mouse Canada Cell Wall Cell model Cells Ciprofloxacin Clindamycin Clinical Trials Clostridium difficile Colitis Communities Data Diarrhea Drug Kinetics Drug resistance Enteral Epithelial Epithelial Cells Epithelium Frequencies Genetic Grant Histologic Human In Vitro Infection Inflammation Inflammatory Injury Intervention Intestines Knock-out Knockout Mice Laboratories Lead Libraries Life Ligands Lymphocyte Mesocricetus auratus Modeling Mus Opportunistic Infections Oral Organoids Oryctolagus cuniculus Outcome Pathogenesis Patients Peptides Peptidoglycan Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Prodrugs Production Publishing Purinergic P1 Receptors Relapse Research Role Severities Signal Pathway Signal Transduction Speed Symptoms System Testing Therapeutic Tilia Toll-Like Receptor 2 Toxin Universities Variant Virginia Whole Organism absorption alanylglutamine cellular targeting cytokine cytotoxic design drug development experience gastrointestinal granulocyte human disease improved in vivo in vivo Model injury and repair innovation leukocyte activation macrophage mast cell neutralizing antibody neutrophil novel novel strategies novel therapeutics prevent quinolone resistance receptor repaired response 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，艰难梭菌相关的腹泻（CDAD）作为抗生素老年医院患者的机会感染。目前，由于催眠毒素，二元毒素产生，耐喹诺酮（BL）菌株的出现，CDAD变得更加令人担忧，因为其在美国和加拿大的频率和严重程度的广泛增加。此外，即使没有最近的抗生素使用，危及生命的CDAD现在也会影响社区中健康的年轻人。更糟糕的是，包括更多抗生素组成的当前治疗方法是失败，并且通常会延长脱落或复发。因此，我们迫切需要采用新颖的方法来阻止毒素诱导的结肠炎，以防止艰难梭菌毒素（S）产生的结肠炎的进展，而不会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进入实验室团队，与毒素发病机理和药物开发中的基础科学同事以及药物合作伙伴（Adenosine Therapeutics，LLC）。我们将采用一种创新的抗毒性方法来解决新兴的奎诺酮艰难梭菌结肠炎，该方法得到了证明很有希望的试验数据。我们建议单独研究三种类型的抗炎剂，并结合使用：腺苷A2A受体激动剂，它们阻断白细胞激活； A2b拮抗剂可通过上皮细胞和肥大细胞堵塞细胞因子的产生，以及促吸收性损伤修复剂丙酰谷氨酰胺。前三个紧密相互关联的特定目标旨在确定这些新型治疗剂如何调节肠细胞靶标，以阻止毒素诱导的凋亡，炎症和分泌。我们计划：1）使用新的人类肠上皮细胞器官和C57BL/6鼠模型来定义纯化的毒素A和B的靶标，以及B-变量和新的BL菌株上清液； 2）使用C57BL/6小鼠与腺苷受体敲除和CRE/LOXP靶向细胞AAA受体缺失来定义相关的腺苷靶标，以抑制毒素作用； 3）使用目标1和2中获得的信息来测试A2A激动剂，A2B拮抗剂和丙酰谷氨酰胺，单独和组合在动物模型中，以准备这些新型药物疗法，以使人类日益严重的CDAD在人类中进行临床试验。我们的第四个目标涉及开发更具吸收的AAR激动剂的发现努力，以及拟议的A2A，激动剂和A2B拮抗剂的综合，以支持这笔赠款。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contribution of adenosine A(2B) receptors in Clostridium difficile intoxication and infection.

腺苷 A(2B) 受体在艰难梭菌中毒和感染中的作用。

DOI：
10.1128/iai.00782-12
发表时间：
2012
期刊：
Infection and immunity
影响因子：
3.1
作者：
Warren,CirleA;Li,Yuesheng;Calabrese,GinaM;Freire,RosemayreS;Zaja-Milatovic,Snjezana;vanOpstal,Edward;Figler,RobertA;Linden,Joel;Guerrant,RichardL
通讯作者：
Guerrant,RichardL

Defined Nutrient Diets Alter Susceptibility to Clostridium difficile Associated Disease in a Murine Model.

DOI：
10.1371/journal.pone.0131829
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Moore JH;Pinheiro CC;Zaenker EI;Bolick DT;Kolling GL;van Opstal E;Noronha FJ;De Medeiros PH;Rodriguez RS;Lima AA;Guerrant RL;Warren CA
通讯作者：
Warren CA