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.

项目摘要/摘要 了解肠道菌群的药物代谢是研究的最前沿，以解释为什么有些 患者对治疗没有充分反应。但是，仍然缺乏有关传染病的研究 以及特定微生物代谢抗生素疗法及其对其对影响的细胞机制 患者的治疗结果。为了促进该研究领域，我们打算阐明肠球菌sp。 肠道细菌代谢含硝基的药物甲硝唑。肠球菌和肠球菌 粪便是人类肠道的主要殖民者，也引起机会性感染。甲硝唑是一个 梭菌型艰难梭菌感染（CDI）的重要疗法，这种疾病对公共卫生构成了紧迫的威胁。 此外，在CDI患者中，抗性霉素肠球菌（VRE）加剧疾病的定植 严重程度。粪肠球菌，但不是粪肠球菌，降解了甲硝唑。我们的初步数据表明这是由于 粪肠球菌中发现的电化学成分与粪肠球菌中不存在的电化学成分之间的独特相互作用。我们将 现在研究这种机制在粪肠球菌中的运作方式以及该细菌促进的程度 甲硝唑的治疗失败。在AIM 1中，我们建议使用微生物遗传学和代谢组学阐明 甲硝唑降解的机理并识别形成的代谢产物。 AIM 2将共同文化 肠球菌和艰难梭菌物种，以识别和测量哪种物种保护艰难梭菌免于被杀 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 CDI疾病的治疗结果和严重程度。这项工作将提高有关肠球菌生理学的知识 与将大肠杆菌与粪肠球菌区分开的新陈代谢和方面有关。这些探索性研究 为了解肠球菌与艰难梭菌之间的种间相互作用奠定基础以及如何 影响疾病的发展和进展。公共卫生。粪肠球菌，粪肠球菌和艰难梭菌是 领先的病原体在医院引起疾病。这项研究对诊断和 对CDI的治疗，这种疾病在美国施加了重大的公共卫生和经济负担。