Polymeric Agents for the Treatment of Clostridium difficile Infections

 描述（由申请方提供）：拟定的研究项目旨在开发一种新型治疗药物，用于治疗艰难梭菌感染。这些感染导致严重的肠道疾病，每年导致20，000人死亡，估计美国每年的费用为48亿美元。C.艰难梭菌通常是复发性的且对抗生素治疗是难治的。C.艰难梭菌作为休眠孢子通过粪-口途径进入体内，并在肠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，导致数万亿的感染性颗粒在宿主粪便中排出。孢子对抗生素和消毒剂具有高度耐药性，这有助于疾病的复发和传播。目前，有几个批准的治疗方案可用于C。艰难梭菌感染（CDI）和没有治疗，打击感染过程中产生的孢子的感染潜力。 我们的首要目标是开发既能作用于生长中的营养细胞又能作用于孢子形式的C。很难在初步研究中，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，可以靶向营养细胞并抑制孢子形式的生长。拟议研究的具体目标是优化和进一步开发这些活性，重点是产生可口服的治疗性聚合物。 尼龙-3材料的抗菌应用受到了天然宿主防御肽活性的启发。所述聚合物相对于这些肽是有利的，因为所述聚合物不被蛋白酶降解（并且因此应该在通过胃时存活），并且所述聚合物相对于肽的生产便宜得多。使用合成聚合物作为C.艰难梭菌治疗剂具有降低治疗使人衰弱的感染的成本和降低疾病传播的潜力。

 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.