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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要了解肠道微生物群的药物代谢是研究的前沿，可以解释为什么有些患者对治疗没有充分反应。但目前对传染病的研究仍然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如何。肠道细菌代谢含硝基药物甲硝唑。粪肠球菌和肠球菌粪肠球菌是人类肠道的主要定植菌，也会引起机会性感染。甲硝唑是一种艰难梭菌感染（CDI）的重要疗法，这种疾病对公众健康构成紧迫威胁。此外，在 CDI 患者中，耐万古霉素肠球菌 (VRE) 的定植会加剧疾病严重程度。粪肠球菌（而非屎肠球菌）会降解甲硝唑。我们的初步数据表明这是由于在粪肠球菌中发现但在屎肠球菌中不存在的电化学成分之间存在独特的相互作用。我们将现在研究这种机制如何在粪肠球菌中运作以及这种细菌促进的程度甲硝唑治疗失败。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机制并鉴定形成的代谢物。目标 2 将共培养肠球菌和艰难梭菌物种，用于识别和测量哪些物种可以保护艰难梭菌免于被杀死通过甲硝唑。研究将进展到动物身上，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。这项工作将增进肠球菌生理学的知识与其代谢以及区分粪肠球菌和屎肠球菌的方面有关。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如何奠定基础影响疾病的发生和进展。公共卫生。粪肠球菌、屎肠球菌和艰难梭菌是导致医院疾病的主要病原体。这项研究对于诊断和治疗具有重要意义 CDI 的治疗，这种疾病给美国带来了重大的公共卫生和经济负担。