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M. tuberculosis carbon metabolism during infection

结核分枝杆菌感染期间的碳代谢

基本信息

批准号：
10716619
负责人：
SABINE EHRT
金额：
$ 65.23万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716619
关键词：
Affect Animal Model Bacteria Biological Models Carbon Complement Development Disease Disease Progression Drug Targeting Environment Enzymes Frequencies Genetic Gluconeogenesis Glycolysis Goals Granuloma Growth Human In Vitro Infection Lesion Lung Maintenance Measurement Metabolic Pathway Metabolism Modeling Morbidity - disease rate Mus Mycobacterium tuberculosis Nutritional Nutritional Requirements PET/CT scan Pathologic Pathology Pathway interactions Persons Phenotype Phosphoenolpyruvate Carboxylase Productivity Reaction Relapse Source Technology Testing Therapeutic Time Tissues Tuberculosis Validation Work X-Ray Computed Tomography chronic infection drug development experience fatty acid metabolism knock-down mortality mouse model mutant mycobacterial new therapeutic target nonhuman primate novel therapeutics tool tuberculosis drugs

项目摘要

The development of TB drugs benefits greatly from validation of novel drug targets in predictive animal models. M. tuberculosis (Mtb) enzymes in central carbon metabolism are emerging as promising targets for drug development but have not been validated in animal models that recapitulate the diverse and heterogeneous environments Mtb encounters in humans. We propose to test the hypothesis that these heterogeneous environments result in airway, lung and granuloma-dependent nutritional restrictions that, at times, make Mtb dependent on both glycolysis and gluconeogenesis to establish and maintain infection in nonhuman primates and/or during paucibacillary infection in mice. We will infect NHPs with Mtb mutants of two enzymes – PFK and PEPCK - that are required for glycolysis or gluconeogenesis, respectively. We will use deletion mutants to determine whether these enzymes are required for establishment of infection and use conditional knockdown mutants to investigate the enzymes importance for growth and survival in different pathologies and for progression of disease. We will furthermore evaluate these mutants in a relapse mouse model to test the hypothesis that the nutritional requirements during long-term persistence in mice, when the bacteria cannot be cultured in vitro, are different from those encountered during active growth and high titer chronic infection and ask whether they mimic environments encountered in NHPs. This proposal builds on the experience of the multi- PI team in mycobacterial genetics, metabolism, and animal models, with the goal to dissect the carbon source requirements for Mtb in the model system that is most similar to human Mtb infection and disease.

结核病药物的开发极大地受益于预测动物模型中新药物靶点的验证。中央碳代谢中的结核分枝杆菌 (Mtb) 酶正在成为有希望的药物靶标发展，但尚未在概括多样性和异质性的动物模型中得到验证 Mtb 在人类中遇到的环境。我们建议检验这些异质性的假设环境导致气道、肺和肉芽肿依赖性营养限制，有时使结核杆菌依赖于糖酵解和糖异生来在非人灵长类动物中建立和维持感染和/或在小鼠的少杆菌感染期间。我们将用两种酶的 Mtb 突变体感染 NHP——PFK 和 PEPCK - 分别是糖酵解或糖异生所需的。我们将使用缺失突变体确定这些酶是否是感染建立所必需的并使用条件敲低突变体以研究酶对于不同病理条件下生长和生存的重要性以及疾病的进展。我们将进一步在复发小鼠模型中评估这些突变体，以测试假设当细菌不能被维持时，小鼠长期持续的营养需求体外培养，与活跃生长和高滴度慢性感染期间遇到的情况不同，询问它们是否模仿 NHP 中遇到的环境。该提案建立在多国经验的基础上 PI团队从事分枝杆菌遗传学、代谢和动物模型研究，目标是剖析碳源与人类 Mtb 感染和疾病最相似的模型系统中对 Mtb 的要求。