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: 10511022
• 负责人: Julian G Hurdle
• 金额: $ 22.2万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511022
• 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; Literature; Malignant Neoplasms; Measures; Metabolic; Metabolism; Metronidazole; Microbe; Microbial Genetics; Modeling; 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; diarrheal disease; drug efficacy; drug mechanism; drug metabolism; dysbiosis; enteric infection; extracellular; gut bacteria; gut colonization; gut microbiota; in vivo; metabolomics; 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 了解肠道微生物群的药物代谢处于研究的前沿，以解释为什么一些 患者对治疗没有充分的反应。然而，对传染病的研究仍然很缺乏。 以及特定微生物代谢抗生素疗法的细胞机制及其对 患者的治疗结果。为了推进这一研究领域，我们打算阐明肠球菌是如何。 肠道细菌代谢含硝基的药物甲硝唑。粪肠球菌和肠球菌 粪便是人类肠道的主要定殖者，也会引起机会性感染。甲硝唑是一种 艰难梭状芽胞杆菌感染(CDI)的重要治疗方法，这是一种对公共健康构成紧急威胁的疾病。 此外，在CDI患者中，携带万古霉素耐药肠球菌(VRE)的定植会加剧疾病 严肃性。粪肠球菌能降解甲硝唑，但不能降解粪肠球菌。我们的初步数据表明这是由于 在粪肠球菌中发现的和在粪肠球菌中不存在的电化学成分之间的独特相互作用。我们会 现在研究这种机制是如何在粪肠球菌中运行的，以及这种细菌在多大程度上促进 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 甲硝唑的降解机理(S)并鉴定形成的代谢物。目标2将共培养 肠球菌和艰难梭菌识别和测量哪些物种保护艰难梭菌不被杀死 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。这项工作将增进对肠球菌生理学的了解。 与其新陈代谢有关，以及粪肠球菌与粪肠球菌的区别。这些探索性研究 为了解肠球菌和艰难梭菌之间的种间相互作用以及这种相互作用 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分别为 在医院引起疾病的主要病原体。本研究对本病的诊断和治疗具有重要意义。 CDI的治疗，这是一种在美国造成重大公共卫生和经济负担的疾病。