Metabolite modulation of Mtb regulators of cell wall biogenesis

细胞壁生物发生的结核分枝杆菌调节剂的代谢调节

• 批准号: 9234364
• 负责人: Georgiana E. Purdy
• 金额: $ 49.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-25 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234364
• 关键词: Amino Acids; Antibiotics; Apoproteins; Bacteria; Binding; Binding Sites; Biogenesis; Biosynthetic Proteins; Carbon; Carrier Proteins; Cause of Death; Cell Wall; Cells; Chronic; Communicable Diseases; Computer Simulation; Consensus; Crystallization; DNA Binding; DNA Structure; DNA-Protein Interaction; DNase-I Footprinting; Data; Diglycerides; Docking; Esters; Fatty Acids; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Immune; Immune response; In Vitro; Infection; Ligand Binding; Ligands; Link; Lipids; Maintenance; Matrix Metalloproteinases; Membrane Proteins; Membrane Structure and Function; Metabolic; Metabolism; Microbial Biofilms; Modeling; Molecular; Mycobacterium tuberculosis; Mycolic Acid; Nucleic Acid Regulatory Sequences; Nutrient; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Physiology; Play; Protein Export Pathway; Proteins; Regulation; Regulon; Resistance; Role; Site-Directed Mutagenesis; Source; Stimulus; Stress; Structure; System; Therapeutic; Transcriptional Regulation; Trehalose; Tuberculosis; Virulence; Waxes; Work; clinically relevant; combat; insight; interest; lipid biosynthesis; lipid transport; mycobacterial; mycolate; novel; pathogen; protein expression; protein transport; small molecule; transcription factor; tuberculosis granuloma

PROJECT SUMMARY Despite the availability of antibiotics to combat Tuberculosis (TB), it is one of the leading causes of death due to infectious disease. Mycobacterium tuberculosis (Mtb) is a successful pathogen because it survives within immune cells and effectively establishes and maintains a latent TB infection. Therefore, understanding the mechanisms underlying the establishment or maintenance of dormancy can inform new strategies for TB therapeutics. Mycobacterial membrane protein large (MmpL) proteins are dedicated cell wall lipid transporters. Along with their accessory Mycobacterial membrane protein small (MmpS) proteins, these transporters are crucial players in mycobacterial physiology and pathogenesis. MmpL3 is essential; and MmpL4, MmpL5, MmpL7, MmpL8, MmpL10 and MmpL11 contribute to Mtb virulence. The related proteins MmpL3 and MmpL11 that transport mycolic acid-containing lipids are of particular interest to us. MmpL3 transports trehalose monomycolate and is required for mycobacterial replication and viability. We showed that MmpL11 transports monomeromycolyl diacylglycerol and a mycolate ester wax. These are species of lipids that are sometimes referred to as “storage lipids” and are associated with dormant bacteria in vitro and accumulate in granulomas of TB patients. Therefore, it appears that MmpL11 plays a role in a clinically relevant, but poorly understood, aspect of Mtb pathogenesis. While significant advances have been made identifying MmpL substrates, the regulation of MmpL protein expression and their role in cell wall remodeling in different environmental conditions has not been explored. The proposed studies will characterize the structure and function of Mtb transcriptional regulators that control expression of essential and virulence-associated MmpL and MmpS proteins. Our preliminary data indicate that fatty acids directly modulate activity of these unique transcription factors. This suggests a model where Mtb can directly assess and respond to fatty acid intermediates, metabolic state and nutrient availability to control mmpL and mmpS gene regulation. By defining the molecular mechanisms underlying the regulation of MmpL transporters and identifying their regulons, we will generate novel insights into the transition between actively dividing Mtb and latent or non-replicating persistent Mtb. !

项目概要 尽管有抗生素可以对抗结核病 (TB)，但它仍然是导致死亡的主要原因之一 由于传染病。结核分枝杆菌 (Mtb) 是一种成功的病原体，因为它能够存活下来 免疫细胞内并有效地建立和维持潜伏性结核感染。因此，了解 建立或维持休眠的机制可以为结核病的新策略提供信息 疗法。 分枝杆菌大膜蛋白 (MmpL) 是专用的细胞壁脂质转运蛋白。沿着 这些转运蛋白及其附属的分枝杆菌小膜蛋白 (MmpS) 至关重要 分枝杆菌生理学和发病机制的参与者。 MmpL3 必不可少；和 MmpL4、MmpL5、MmpL7、 MmpL8、MmpL10 和 MmpL11 有助于 Mtb 毒力。相关蛋白 MmpL3 和 MmpL11 我们对运输含分枝菌酸的脂质特别感兴趣。 MmpL3 转运海藻糖 单分枝杆菌，是分枝杆菌复制和生存所必需的。我们证明了 MmpL11 运输 单体菌基二酰基甘油和霉菌酸酯蜡。这些脂质种类有时 被称为“储存脂质”，与体外休眠细菌相关并在肉芽肿中积累 结核病患者。因此，MmpL11 似乎在临床相关但知之甚少的过程中发挥着作用， Mtb 发病机制的一个方面。 虽然 MmpL 底物的识别已取得重大进展，但 MmpL 蛋白的调控 表达及其在不同环境条件下细胞壁重塑中的作用尚未被探索。 拟议的研究将表征控制 Mtb 转录调节因子的结构和功能 必需的和毒力相关的 MmpL 和 MmpS 蛋白的表达。我们的初步数据表明 脂肪酸直接调节这些独特转录因子的活性。这提出了一个模型，其中 Mtb 可以直接评估和响应脂肪酸中间体、代谢状态和营养可用性来控制 mmpL 和 mmpS 基因调控。通过定义 MmpL 调节的分子机制 转运蛋白并识别它们的调节子，我们将对主动之间的转变产生新的见解 区分 Mtb 和潜伏或非复制持久性 Mtb。 ！