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

• 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
• 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

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，C。艰难梭菌相关性腹泻（CDAD）发生在使用抗生素的老年住院患者中，为机会性感染。目前，CDAD已经变得更加令人担忧，因为在整个美国和加拿大，由于高产毒、二元产毒、喹诺酮耐药（BI）菌株的出现，其频率和严重程度普遍增加。此外，危及生命的CDAD现在正在影响社区中的健康年轻人，即使最近没有使用抗生素。更糟糕的是，目前的治疗包括更多的抗生素是失败的，往往脱落或复发。因此，我们迫切需要新的方法来阻断毒素诱导的结肠炎，以防止C.艰难梭菌毒素）而不进一步破坏保护性植物群。弗吉尼亚大学的这项申请将我们经验丰富的肠道实验室团队与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（腺苷治疗有限责任公司）聚集在一起。我们将讨论新出现的喹诺酮类耐药的C。艰难性结肠炎与创新的抗毒性方法，这是由试点数据证明相当大的承诺支持。我们建议调查三种类型的抗炎剂单独和组合：腺苷A2A受体激动剂，阻止白细胞活化; A2B拮抗剂，阻止上皮细胞和肥大细胞产生细胞因子，和促吸收损伤修复剂，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的治疗方法如何调节肠细胞靶点，以阻断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C57 BL/6鼠模型来定义纯化的毒素A和B以及B-变体和新的B1菌株上清液的靶标;和3）使用在目的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（单独和组合），以便为这些用于人类中日益严重的CDAD的新型药物疗法的临床试验做准备。我们的第四个目标涉及开发吸收率更高的AaR激动剂的发现工作，以及支持该资助所需的拟议A2 A、激动剂和A2 B拮抗剂的合成。

项目成果

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