Mechanism Of Enterococcus Faecalis Nitro Drug Metabolism And In Vivo Implications

粪肠球菌硝基药物代谢机制及其体内影响

• 批准号: 10634708
• 负责人: Julian G Hurdle
• 金额: $ 23.2万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634708
• 关键词: Affect; Anabolism; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Area; Bacteria; Biochemistry; Biology; Clinical; Clostridium difficile; Coculture Techniques; Communicable Diseases; Coupled; Data; Data Analyses; Development; Diagnosis; Disease; Economic Burden; Electron Transport; Electrons; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Enzymes; Exposure to; Foundations; Genes; Genetic; Health; Hospitals; Human; In Vitro; Infection; Knowledge; Learning; Literature; Malignant Neoplasms; Measures; Metabolic; Metabolism; Metronidazole; Microbe; Microbial Genetics; Molecular; Mus; Opportunistic Infections; Organism; Oxidoreductase; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Public Health; Publications; Quinones; Reaction; Research; Resistance; Respiratory Chain; Risk; Risk Factors; Role; Severities; Severity of illness; Shapes; Testing; Time; Treatment Failure; Treatment outcome; United States; Vancomycin resistant enterococcus; Work; candidate identification; diarrheal disease; drug efficacy; drug metabolism; dysbiosis; enteric infection; extracellular; gut bacteria; gut colonization; gut microbiota; in vivo; metabolomics; model building; murine colitis; mutant; novel; pathobiont; pathogen; transcriptome

PROJECT SUMMARY/ABSTRACT Understanding drug metabolism by intestinal microbiota is at the forefront of research to explain why some patients do not adequately respond to therapy. However, there remains a lack of research on infectious diseases and the cellular mechanisms by which specific microbes metabolize antibiotic therapies and its impact on treatment outcomes in patients. To advance this research area, we intend to elucidate how Enterococcus sp. gut bacteria metabolize the nitro-containing drug metronidazole. Enterococcus faecalis and Enterococcus faecium are the main colonizers of the human gut, and also cause opportunistic infections. Metronidazole is an important therapy for Clostridioides difficile infection (CDI), a disease that poses an urgent threat to public health. Furthermore, in CDI patients, colonization of with vancomycin-resistant enterococci (VRE) exacerbates disease severity. E. faecalis, but not E. faecium, degrades metronidazole. Our preliminary data suggests this is due to unique interactions between electrochemical components found in E. faecalis and absent in E. faecium. We will now investigate how this mechanism operates in E. faecalis and the extent to which this bacterium promotes treatment failure for metronidazole. In aim 1 we propose to use microbial genetics and metabolomics to elucidate the mechanism(s) of metronidazole degradation and identify the metabolites formed. Aim 2 will co-culture enterococcal and C. difficile species to identify and measure which species protect C. difficile from being killed by metronidazole. Studies will progress to animals, where we measure the effect of enterococci on metronidazole treatment outcomes and severity of CDI disease. This work will advance knowledge of enterococcal physiology relating to its metabolism and aspects that differentiate E. faecalis from E. faecium. These exploratory studies lay the foundation to understand inter-species interactions between enterococci and C. difficile and how this influences disease development and progression. Public health. E. faecalis, E. faecium and C. difficile are leading pathogens causing diseases in hospitals. This study has significant implications for the diagnosis and treatment of CDI, a disease that imposes a major public health and economic burden in the United States.

项目总结/摘要 通过肠道微生物群了解药物代谢是研究的前沿，可以解释为什么一些 患者对治疗没有充分的反应。然而，仍然缺乏对传染病的研究 以及特定微生物代谢抗生素治疗的细胞机制及其对 患者的治疗结果。为了推进这一研究领域，我们打算阐明如何肠球菌。 肠道细菌代谢含硝基药物甲硝唑。粪肠球菌和肠球菌 粪便是人类肠道的主要定植者，并且还引起机会性感染。甲硝唑是一种 艰难梭菌感染（CDI）是一种对公共卫生构成紧迫威胁的疾病， 此外，在CDI患者中，万古霉素耐药肠球菌（VRE）的定植可加重疾病 严重性。E. faecalis，而不是E.粪菌，降解甲硝唑。我们的初步数据表明，这是由于 在E. faecalis，E.屎室我们将 现在研究这个机制在E.以及这种细菌促进 甲硝唑治疗失败在目标1中，我们建议使用微生物遗传学和代谢组学来阐明 甲硝唑降解的机制，并确定形成的代谢产物。目标2将共同培养 肠球菌和C.艰难的物种，以确定和衡量哪些物种保护C。不被杀 甲硝唑。研究将进展到动物，在那里我们测量肠球菌对甲硝唑的影响 治疗结果和CDI疾病的严重程度。这项工作将推进肠球菌生理学的知识 与其代谢和E.来自E.屎室这些探索性研究 为进一步了解肠球菌和C.艰难的，这是如何 影响疾病的发展和进程。公共卫生E.粪肠球菌E. faecium和C.艰难区 导致医院疾病的主要病原体。这项研究对诊断有重要意义， CDI是一种在美国造成重大公共卫生和经济负担的疾病。