Polymeric Agents for the Treatment of Clostridium difficile Infections

用于治疗艰难梭菌感染的聚合物制剂

• 批准号: 9186498
• 负责人: SAMUEL H. GELLMAN
• 金额: $ 21.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186498
• 关键词: Anaerobic Bacteria; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Bacteria; Bacterial Infections; Base Composition; Bile Acids; Cations; Cells; Cessation of life; Clinical; Clostridium difficile; Development; Digestive System Disorders; Disease; Disinfectants; Evaluation; Feasibility Studies; Feces; Gastrointestinal tract structure; Germination; Goals; Hamsters; Health Care Costs; Healthcare Systems; Host Defense; Hydrophobicity; Individual; Infection; Intestinal Diseases; Intestines; Mission; Modeling; Mus; Nylons; Oral; Oral Administration; Peptide Hydrolases; Peptides; Pharmacodynamics; Phase; Polymers; Prevention; Production; Property; Recurrence; Refractory; Relapse; Reproduction spores; Research; Resistance; Route; Screening Result; Stomach; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxin; United States; antimicrobial; base; candidate selection; combat; copolymer; cost; cytotoxicity; design; disease transmission; efficacy evaluation; improved; in vivo; killings; new therapeutic target; novel; novel strategies; particle; pathogen; prevent; programs; public health relevance; transmission process; treatment strategy

 DESCRIPTION (provided by applicant): The proposed research program aims to generate a new type of therapeutic agent for treatment of Clostridium difficile infections. These infections cause severe intestinal disease, leading to 20,000 deaths annually and an estimated annual cost of $4.8 billion in the United States. Infections due to C. difficile are often recurrent and refractory to antibiotic treatment. C. difficile enters the body as a dormant spore via the fecal-oral route and germinates in the intestine to produce vegetative cells. These cells replicate in the host and generate the toxins that cause illness. During infection, many of the vegetative cells develop into spores, resulting in trillions of infectious particles excreted in host feces. Spores are highly resistant to antibiotics and disinfectants, which facilitates relapse and dissemination of disease. Currently, there are few approved treatment options available for C. difficile infections (CDI) and no treatment that combats the infectious potential of spores produced during an infection. Our over-arching goal is to develop agents that act on both growing vegetative cells and the spore form of C. difficile. In preliminary studies, our collaborative team has discovered that a non-traditional type of agent, nylon-3 polymers, can target vegetative cells and inhibit outgrowth from the spore form. The specific objective of the proposed research is to optimize and further develop these activities, with a focus on generating an orally-deliverable therapeutic polymer. Exploration of nylon-3 materials for antimicrobial applications was inspired by the activities of natural host- defense peptides. The polymers are advantageous relative to these peptides in that the polymers are not degraded by proteases (and should therefore survive passage through the stomach), and the polymers are much less expensive to produce relative to peptides. The use of synthetic polymers as C. difficile therapeutics has the potential to decrease the costs of treating debilitating infections and to lower disease transmission.

 描述(由申请人提供)：拟议的研究计划旨在产生一种治疗艰难梭菌感染的新型治疗剂。这些感染会导致严重的肠道疾病，在美国每年导致2万人死亡，估计每年造成48亿美元的损失。艰难梭菌引起的感染通常是反复发作的，对抗生素治疗无效。艰难梭菌通过粪口途径以休眠孢子的形式进入体内，并在肠道中萌发，产生营养细胞。这些细胞在宿主体内复制并产生导致疾病的毒素。在感染过程中，许多营养细胞发育成孢子，导致宿主粪便中排出数万亿个感染颗粒。孢子对抗生素和消毒剂具有高度抵抗力，这有助于疾病的复发和传播。目前，几乎没有批准的艰难梭菌感染(CDI)治疗方案，也没有治疗方法来对抗感染过程中产生的孢子的感染潜力。 我们的总体目标是开发既能作用于生长中的营养细胞，又能作用于艰难梭菌孢子形态的制剂。在初步研究中，我们的合作团队发现了一种非传统类型的试剂，尼龙-3聚合物，可以针对营养细胞并抑制孢子形态的生长。拟议研究的具体目标是优化和进一步开发这些活动，重点是产生一种可口服的治疗性聚合物。 尼龙-3材料用于抗菌应用的探索是受到天然宿主防御肽活性的启发。与这些肽相比，聚合物具有优势，因为聚合物不会被蛋白酶降解(因此应该在胃中存活)，并且相对于肽，聚合物的生产成本要低得多。使用合成聚合物作为艰难梭菌的治疗药物，有可能降低治疗衰弱感染的成本，并降低疾病传播。