Defined microbial communities to prevent and eradicate infection by AMR pathogens

项目摘要 在抗生素发现之前，传染病是美国人死亡的三大原因。 每年死亡人数的近50%。今天只有一种传染病，肺炎， 在美国的十大死亡原因中，主要是由于抗生素在治疗细菌感染方面的成功， 感染.不幸的是，抗生素提供的公共健康益处面临严重风险， 抗生素耐药性细菌的出现，这是进化压力对人类产生的不可避免的后果。 细菌通过这些药物。最终，我们希望阻止的细菌病原体将对所有细菌产生抗药性。 临床相关的抗生素，使人类回到前抗生素的世界，在这个世界里，传染病是最重要的疾病。 主要死因因此，我们需要找到创新的、可迅速实施的方法， 补充抗生素，以保持其在控制细菌感染中的效用。许多细菌病原体， 称为致病菌，在没有疾病的情况下存在于人类微生物群中， 发病机制后的微生物群落破坏驱动的突然环境变化，如急性 炎症虽然普遍认为肠道微生物提供病原体定殖， 抵抗和抑制致病菌的毒力在健康状态下，机制的理解，如何 他们提供的这些好处是缺乏的。在这个项目中，我们探索使用人类微生物组来识别 生态学原则，允许设计和实施微生物群落， 细菌病原体我们选择了艰难梭菌和肠外致病性大肠杆菌。大肠杆菌（ExPEC）作为 研究的两种主要病原体，因为它们被CDC认为是抗生素耐药性威胁， 每年有数百万的抗生素处方。即使使用抗生素治疗， 这些病原体很常见，目前缺乏持久的预防战略。使用一种新 简化人类微生物群落的方法和先进的体外人类组织培养和人源化 在小鼠模型中，我们寻求鉴定用于抑制这些病原体的关键微生物聚生体。我们最终 期望优化少量可用于根除或预防的确定的微生物群落 这些感染的人。

Project Summary Before the discovery of antibiotics, infectious diseases were the three leading causes of death in the United States and constituted nearly 50% of the deaths annually. Today only one infectious disease, pneumonia, is among the top 10 causes of death in the US, largely due to the success of antibiotics in treating bacterial infections. Unfortunately, the public health benefits provided by antibiotics are at serious risk due to the emergence of antibiotic resistant bacteria, an inevitable consequence of the evolutionary pressure exerted on bacteria by these drugs. Eventually the bacterial pathogens we hope to keep at bay will become resistant to all clinically relevant antibiotics, plunging humans back into a pre-antibiotic world in which infectious disease is the leading cause of death. Therefore, we need to find innovative, and rapidly implementable, ways to reduce or supplement antibiotics to preserve their utility in controlling bacterial infections. Many bacterial pathogens, termed pathobionts, reside within the human microbiota in the absence of disease and only instigate pathogenesis after disruption of the microbial community driven by abrupt environmental changes such as acute inflammation. While there is general acceptance that the commensal microbes provide pathogen colonization resistance and suppression of pathobiont virulence in a healthy state, the mechanistic understanding for how they provide these benefits is lacking. In this project, we explore using the human microbiome to identify ecological principles that allow for the design and implementation of microbial communities that suppress bacterial pathogens. We have selected Clostridioides difficile and extraintestinal pathogenic E. coli (ExPEC) as the two main pathogens to study as they are deemed antibiotic resistance threats by the CDC and necessitate millions of antibiotic prescriptions each year. Even with antibiotic treatment, recurrent infections with both of these pathogens is common, and there is currently a lack of long-lasting preventative strategies. Using a novel method to simplify human microbiome communities and advanced in vitro human tissue culture and humanized murine models, we seek to identify key microbial consortia for suppressing these pathogens. We ultimately expect to optimize a small number of defined microbial communities that can be used to eradicate or prevent these infections in people.