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。

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）

Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment.

腺苷 A2A 受体激活可降低万古霉素治疗后小鼠艰难梭菌感染的复发和死亡率。

DOI：
发表时间：
2012
期刊：
影响因子：
3.7
作者：
Li, Yuesheng;Figler, Robert A;Kolling, Glynis;Bracken, Tara C;Rieger, Jayson;Stevenson, Ralph W;Linden, Joel;Guerrant, Richard L;Warren, Cirle Alcantara
通讯作者：
Warren, Cirle Alcantara

Lactic acid production by Streptococcus thermophilus alters Clostridium difficile infection and in vitro Toxin A production.

嗜热链球菌产生的乳酸改变了艰难梭菌感染和体外毒素 A 的产生。

DOI：
发表时间：
2012-11
期刊：
影响因子：
12.2
作者：
Kolling, Glynis L;Wu, Martin;Warren, Cirle A;Durmaz, Evelyn;Klaenhammer, Todd R;Guerrant, Richard L
通讯作者：
Guerrant, Richard L

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

特定营养饮食改变小鼠模型中对艰难梭菌相关疾病的易感性。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Moore, John H;Pinheiro, Caio C D;Zaenker, Edna I;Bolick, David T;Kolling, Glynis L;van Opstal, Edward;Noronha, Francisco J D;De Medeiros, Pedro H Q S;Rodriguez, Raphael S;Lima, Aldo A;Guerrant, Richard L;Warren, Cirle A
通讯作者：
Warren, Cirle A

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：
发表时间：
2012-12
期刊：
影响因子：
3.1
作者：
Warren, Cirle A;Li, Yuesheng;Calabrese, Gina M;Freire, Rosemayre S;Zaja;van Opstal, Edward;Figler, Robert A;Linden, Joel;Guerrant, Richard L
通讯作者：
Guerrant, Richard L

Vancomycin treatment's association with delayed intestinal tissue injury, clostridial overgrowth, and recurrence of Clostridium difficile infection in mice.

万古霉素治疗与小鼠迟发性肠组织损伤、梭菌过度生长和艰难梭菌感染复发相关。

DOI：
发表时间：
2013-02
期刊：
影响因子：
4.9
作者：
Warren, Cirle A;van Opstal, Edward J;Riggins, Mary S;Li, Yuesheng;Moore, John H;Kolling, Glynis L;Guerrant, Richard L;Hoffman, Paul S
通讯作者：
Hoffman, Paul S