Defined microbial communities to prevent and eradicate infection by AMR pathogens

项目摘要 在发现抗生素之前，传染病是美国的三大主要死因 每年死亡人数占死亡人数的近50%。今天，只有一种传染病，肺炎，是 在美国前十大死因中，主要是由于抗生素在治疗细菌方面的成功 感染。不幸的是，抗生素提供的公共健康益处正处于严重危险之中，因为 抗药性细菌的出现，这是施加在进化上的压力的必然结果 细菌被这些药物感染。最终，我们希望遏制的细菌病原体将对所有 临床上相关的抗生素，使人类重新陷入抗生素出现前的世界，在这个世界里，传染病是 头号死因。因此，我们需要找到创新的、可快速实施的方法来减少或 补充抗生素以保持其在控制细菌感染方面的效用。许多细菌病原体， 被称为致病细菌，在没有疾病的情况下驻留在人类微生物区系内，只是煽动 由急性等突发环境变化导致微生物群落破坏后的发病机制 发炎。虽然人们普遍认为共生微生物提供了病原体定植 在健康状态下对病原菌毒力的抵抗和抑制，对如何进行机制的理解 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 允许设计和实施微生物群落的生态学原则 细菌病原体。我们选择艰难梭状芽胞杆菌和肠外致病性大肠杆菌(ExPEC)作为 两种主要病原体需要研究，因为它们被疾控中心认为是抗生素耐药性威胁，并有必要 每年数以百万计的抗生素处方。即使接受抗生素治疗，这两种疾病的反复感染 这些病原体很常见，目前缺乏长效的预防策略。用一本小说 一种简化人体微生物群落和推进人体组织培养及人源化的方法 在小鼠模型中，我们试图确定抑制这些病原体的关键微生物联合体。我们最终 期望优化少数可用于根除或预防的已定义微生物群落 这些人身上的感染。

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.