Temporal dynamics of MDRO eradication after FMT

项目摘要 世界卫生组织和美国疾病控制和预防中心已指定 抗生素耐药性是全球健康的主要威胁，每年有超过23，000例与抗生素相关的死亡 仅在美国就出现了耐药感染。然而，开发新抗生素的药物管道是干燥的。小 研究支持粪便微生物群移植（FMT）的安全性和有效性， 抗细菌耐药生物体的定殖，但其机制还不清楚。我们将 利用来自临床试验PREMIX（NCT 02922816）的患者相关样本， 假设厌氧细菌，病毒和它们的基因预测功能与 FMT后MDRO定植减少。本提案的具体目的包括：目的1：使用临床 细菌培养的金标准，以评估FMT在MDRO根除中的疗效。目标2A：建立一个新的 宏基因组分析管道（MAP），用于量化细菌和病毒分类群、AR、毒力和 定植抗性基因目的2B：使用16 S rRNA测序来估计难以预测的时间动态。 培养细菌分类群FMT与对照。目标2C：使用宏基因组全基因组测序和MAP 估计FMT与对照组中AR、毒力和定殖抗性基因的时间动态。目标3： 使用环境病毒组NGS技术测试病毒（包括噬菌体）分类群与 FMT后的MDRO丰度。我们期望，完成这些目标和相关培训将导致 临床适用的初步数据和转化微生物治疗开发的下一步 MDRO殖民化。我的长期职业目标是成为ID微生物组数据的协作领导者 科学集中于：1）微生物治疗的机制，如FMT在减少与多- 耐药微生物（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定植和感染。埃默里大学和格鲁吉亚理工大学是理想的、高度合作的学校 研究环境，这两个国家的领导人在生物医学研究。两家机构都提供丰富的 资源来完成所描述的目标和职业发展的进展，成为一个独立的 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性部位 7项微生物治疗临床试验和一项临床FMT计划的调查，该计划已完成超过 治疗难治性艰难梭菌300例。

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.