Development of Faux-Biotics to combat the spread of hospital-acquired antibiotic-resistant infections

项目摘要 CDC认为抗生素耐药性的升级是美国最大的公共卫生问题之一。 我们这个时代抗生素耐药性是人类和动物健康的一个主要问题，耐药性感染和 抗药性基因可以在动物和与它们相互作用的人类之间传播。之一 最紧迫的威胁是耐碳青霉烯类肠杆菌科（CRE）。抗生素使用是一个主要的风险因素 对于粪便CRE携带的发展，这既是血液感染的来源，也是传播到其他人的来源。 易受感染的病人通过与医院工作人员接触。由于缺乏治疗方案，这些 感染可在高达50%的获得它们的患者中致命。目前恢复殖民化的疗法 使用粪便微生物群移植、益生元或益生菌来靶向微生物群。但对于 对于必须继续使用抗生素的患者，这些治疗方案不太可能成功。一个健康 微生物群以两种方式提供定植抗性：通过占据肠道中所有可用的小生境， 直接防止其他微生物群定植，并通过改变肠道环境， 让入侵的细菌不那么容易进入后者包括生产短链 脂肪酸，使微生物群与宿主细胞相互作用，改善肠道健康和定植 阻力本申请的目的是设计一种治疗方法，以在感染期间恢复定殖抗性。 抗生素疗法，利用微生物群在稳态条件下使用的途径。我们 一种假设是，5-阿萨，一种激活微生物群使用的结肠细胞通路的药物， 成功恢复对碳青霉烯耐药肠杆菌科的定殖耐药性， 免疫活性和免疫受损宿主的抗生素治疗。为了验证我们的假设，我们将首先 使用抗生素给药和CRE暴露的SPF小鼠模型，使用或不使用5-阿萨治疗。 在CRE暴露（预防）之前或CRE感染之后，将小鼠置于含5-ASA的饮食中 （处理）和定殖将通过粪便和盲肠内容物监测。然后我们将感染无菌 在开始使用抗生素前和使用抗生素后4-7天， 开始抗生素治疗。这些小鼠也将被置于含5-ASA的饮食中，以证明 CRE定植的有效预防或减少可以在不同的患者微生物群中实现， 各种抗生素疗法。最后，我们将利用环磷酰胺小鼠免疫抑制模型， 证明由于5-ASA介导的肠道CRE CFU减少而导致CRE菌血症减少。 成功完成拟议的研究将提供临床前证据，表明5-阿萨，一种临床上 批准的药物，可用于加强殖民抵抗和降低CRE菌血症的风险， 免疫受损宿主通过激活上皮PPAR-g信号传导对抗生素治疗的作用， 确立了宿主作为增强定殖抗性的处理靶点。

Project Summary The CDC considers the escalation of antibiotic resistance to be one of the biggest public health concerns of our time. Antibiotic resistance is a major issue both human and animal health, and resistant infections and resistance genes can be transmitted between animals and the humans who interact with them. One of the most urgent threats is Carbapenem-resistant Enterobacteriaceae (CRE). Antibiotic usage is a major risk factor for the development of fecal CRE carriage, which is both a source of bloodstream infection and spread to other susceptible patients through contact with hospital workers. Due to the lack of treatment options, these infections can be deadly in up to 50% of patients who acquire them. Current therapies to restore colonization resistance target the microbiota using fecal microbiota transplantation, prebiotics, or probiotics. However, for patients who must remain on antibiotics, these treatment options are unlikely to be successful. A healthy microbiota provides colonization resistance in two ways: by occupying all available niches in the intestine to directly prevent other microbiota from colonizing, and through modification of the intestinal environment to make it less welcoming for invading bacteria. The latter includes production of substances such as short-chain fatty acids, which allow the microbiota to interact with host cells and improve intestinal health and colonization resistance. The objective of this application is to devise a treatment to restore colonization resistance during antibiotic therapy that exploit the pathways used by the microbiota under homeostatic conditions. Our hypothesis is that 5-ASA, a drug that activates pathways in colonocytes used by the microbiota, will be successful at restoring colonization resistance against carbapenem resistance Enterobacteriaceae after antibiotic treatment in immunocompetent and immunocompromised hosts. To test our hypothesis, we will first use an SPF mouse model of antibiotic administration and CRE exposure with or without treatment with 5-ASA. Mice will be placed on a 5-ASA-containing diet either prior to CRE exposure (prevention) or after CRE infection (treatment) and colonization will be monitored through feces and cecal contents. We will then infect Germ-free mice recolonized with paired patient fecal samples collected before antibiotics are started and 4-7 days after antibiotic therapy is initiated. These mice will also be placed on a 5-ASA-containing diet to demonstrate that effective prevention or reduction of CRE colonization can be achieved in diverse patient microbiotas with various antibiotic therapies. Finally, we will utilize a cyclophosphamide model of immunosuppression in mice to demonstrate reduced CRE bacteremia as a result of 5-ASA-mediated reduction of intestinal CRE CFU. Successful completion of the proposed research will provide pre-clinical evidence that 5-ASA, a clinically approved drug, can be used to strengthen colonization resistance and lower the risk for CRE bacteremia in an immunocompromised host on antibiotic therapy by activating epithelial PPAR-g signaling, a paradigm shift that establishes the host as a treatment target for strengthening colonization resistance.