Temporal dynamics of MDRO eradication after FMT

项目总结 世界卫生组织和美国疾病控制和预防中心已指定 抗菌素耐药性是全球健康的主要威胁，每年有超过2.3万人死于抗菌药 仅在美国就有耐药感染。然而，开发新抗生素的药物管道是枯竭的。小的 研究支持粪便微生物区系移植(FMT)消除肠道的安全性和有效性 用抗菌素耐药的生物体进行定植，但其机制尚不清楚。我们会 利用来自临床试验PREMIX(NCT02922816)的患者关联样本来测试我们的总体设计 厌氧菌、病毒及其基因预测功能与 FMT后MDRO定植减少。这项建议的具体目标包括：目标1：使用临床 以细菌培养金标准评价FMT根除MDRO的疗效。目标2a：建立一部小说 元基因组分析流水线(MAP)，用于量化细菌和病毒分类群、AR、毒力和 定殖抗性基因。目的2B：应用16S rRNA测序技术评估难治性脑出血患者的时间动力学 FMT组与对照组培养细菌分类群。目标2C：使用元基因组全基因组测序和图谱 评估FMT与对照组AR、毒力和定植抗性基因的时间动态。目标3： 使用环境病毒NGS技术测试病毒(包括噬菌体)分类群与 FMT后MDRO的丰度。我们期望这些目标和相关培训的完成将导致 临床适用的初步数据和转化型微生物治疗开发的下一步 MDRO殖民。我的长期职业目标是成为ID微生物组数据领域的合作领导者 科学关注：1)微生物疗法，如FMT，在减少多种细菌侵袭中的作用机制。 耐药生物(MDRO)，以及2)将这些发现转化为临床和公共卫生干预措施 以减少MDRO的定植和感染。埃默里和佐治亚理工学院是理想的、高度合作的 研究环境，这两个国家都是生物医学研究的领先者。两家机构都提供了丰富的 资源，以完成所述的目标，并在职业发展中取得进展，成为独立的 翻译ID微生物组数据科学家。此外，埃默里是微生物治疗的活跃场所 对微生物疗法的7项临床试验和一项已完成的临床FMT计划的调查 难治性难治性梭状芽胞杆菌的300例治疗。

PROJECT SUMMARY The World Health Organization and U.S. Centers for Disease Control and Prevention have designated antimicrobial resistance a major threat to Global Health with over 23,000 annual deaths related to antimicrobial resistant infections in the U.S. alone. However, the drug pipeline to develop new antibiotics is dry. Small studies support the safety and efficacy of fecal microbiota transplantation (FMT) to eliminate intestinal colonization with antibacterial resistant organisms but its mechanisms are not well understood. We will leverage patient-linked samples from a clinical trial PREMIX (NCT02922816) to test our overarching hypothesis that anaerobic bacteria, viruses, and their gene-predicted functions are causally associated with decreased MDRO colonization after FMT. The Specific Aims of this proposal include: Aim 1: Use the clinical gold standard of bacterial culture to estimate efficacy of FMT in MDRO eradication. Aim 2A: Establish a novel metagenomic analytic pipeline (MAP) to quantify abundance of bacterial and viral taxa, AR, virulence, and colonization resistance genes. Aim 2B: Use 16S rRNA sequencing to estimate temporal dynamics of difficult to culture bacterial taxa in FMT vs controls. Aim 2C: Use metagenomic whole-genome sequencing and the MAP to estimate temporal dynamics of AR, virulence, and colonization resistance genes in FMT vs controls. Aim 3: Use environmental virome NGS techniques to test the association of viral (including bacteriophage) taxa with abundance of MDRO after FMT. We expect that completion of these aims and related training will lead to clinically applicable preliminary data and next steps in translational microbial therapeutic development for MDRO colonization. My long-term career goal is to become a collaborative leader in ID microbiome data science focusing on: 1) mechanisms of microbial therapeutics such as FMT in reducing colonization with multi- drug resistant organisms (MDRO), and 2) translating these findings into clinical and public health interventions to reduce MDRO colonization and infection. Emory and Georgia Tech are ideal and highly-collaborative research environments, which are both national leaders in biomedical research. Both institutions provide rich resources to complete the described aims and progress in career development to become an independent translational ID microbiome data scientist. In addition, Emory is an active site of microbial therapeutic investigation with 7 clinical trials of microbial therapeutics and a clinical FMT program that has completed over 300 treatments for refractory Clostridioides difficile.