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NMR-resolved dynamics of C. difficile metabolism

艰难梭菌代谢的核磁共振解析动力学

基本信息

批准号：
10574895
负责人：
LYNN BRY
金额：
$ 8.95万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2022-11-14 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574895
关键词：
Ablation Acids Address Alanine Alanine Transaminase Amines Amino Acids Anaerobic Bacteria Antibiotic Therapy Antibiotics Bile Acids Biomass Carbohydrates Carbon Cells Clinical Clostridium difficile Complex Consumption Disease Ecosystem Enzymes Equilibrium Ethanolamines Fermentation Ferredoxin Formates Genes Genetic Glutamate Dehydrogenase Glycolysis Growth Hospitals Infection L Forms Label Lyase Magic Mediating Metabolic Metabolic Pathway Metabolism Methods Modeling Molecular Mucous Membrane Nitrogen Nosocomial Infections Nuclear Magnetic Resonance Nutrient Nutrient availability Outcome Oxidases Oxidation-Reduction Pathway interactions Phase Phenotype Physiology Production Pyruvate Regulon Resolution Role Serine Source Surface System Therapeutic Intervention Time Toxin Transaminases Virulence amino acid metabolism commensal microbes computer framework defined contribution energy balance genome-wide gut colonization improved in vivo metabolic abnormality assessment metabolomics metatranscriptomics microbiota mutant nitrogen metabolism novel pathogen preventive intervention programs rapid growth recruit small molecule therapeutic target tool transamination

项目摘要

Abstract: Clostridioides difficile is the most prevalent cause of hospital associated infections (HAIs). As an obligately anaerobic pathogen, C. difficile can consume diverse carbon sources to support gut colonization and infection. In particular, glycolytic and Stickland amino acid fermentation pathways have been shown to support rapid growth, a finding that also occurs after antibiotic treatment elevates availability of these nutrient sources by removing competitive commensal species. However, the metabolic pathways of obligately anaerobic bacteria remain ill-defined, limiting capacity to identify preventive and therapeutic interventions that target C. difficile’s core physiology. To address these limitations, we will employ carbon-13 (13C) NMR of C. difficile’s dynamic metabolism to inform a genome-scale metabolic model and clearly define metabolic integration points among energy-generating glycolytic and amino acid fermentation pathways. Findings will be evaluated in targeted genetic mutants and with combinations of fermentable carbon sources to evaluate their impact on pathogen growth and virulence.

摘要：艰难梭菌是医院感染的主要病原菌（HAI）。C. difficile可以消耗多种碳源，支持肠道定植和感染。特别是糖酵解和Stickland氨基酸发酵途径已被证明支持快速生长，这一发现也发生在抗生素治疗通过去除竞争性的营养物质，植物种。然而，专性厌氧细菌的代谢途径仍然存在，定义不清，确定针对C的预防和治疗干预措施的能力有限。 difficile的核心生理学为了解决这些局限性，我们将采用100 - 200 μ mol/L的碳-13（13 C）NMR。 C.艰难梭菌的动态代谢，以告知基因组规模的代谢模型，并明确定义产能糖酵解和氨基酸发酵的代谢整合点路径。研究结果将在靶向遗传突变体中进行评估，并与以下组合进行评估：可发酵碳源，以评估其对病原体生长和毒力的影响。