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. !

项目摘要 尽管抗生素可用于打击结核病（TB），但它是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，因为它存活 在免疫小球内，有效地建立并维持潜在的结核病感染。因此，理解 建立或维持休眠的基础机制可以为结核病的新策略提供信息 疗法。 分枝杆菌膜蛋白大（MMPL）蛋白是专用的细胞壁脂质转运蛋白。沿着 伴随其辅助分枝杆菌膜蛋白小（MMP）蛋白，这些转运蛋白至关重要 分枝杆菌生理和发病机理的参与者。 MMPL3是必不可少的；和mmpl4，mmpl5，mmpl7， MMPL8，MMPL10和MMPL11有助于MTB病毒。相关的蛋白质mmpl3和mmpl11 含霉菌酸的脂质对我们特别感兴趣。 MMPL3运输海藻糖 单霉菌酸酯是分生不清的复制和生存能力所必需的。我们表明MMPL11运输 单霉素二酰基甘油和粘液酯蜡。这些是有时的脂质物种 称为“储存脂质”，体外与休眠细菌有关，并积聚在颗粒中 结核病患者。因此，MMPL11似乎在临床上相关但知之甚少，但很了解 MTB发病机理的方面。 尽管已经确定了MMPL底物的重大进展，但MMPL蛋白的调节 尚未探索表达及其在不同环境条件下的细胞壁重塑中的作用。 拟议的研究将表征控制MTB转录调节器的结构和功能 必需和病毒相关的MMPL和MMP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的转录因子的活性。这表明了MTB的模型 可以直接评估并响应脂肪酸中间体，代谢状态和养分可用性 MMMPL和MMMPS基因调节。通过定义MMPL调控的基础机制 转运蛋白并确定其规范，我们将对积极的过渡产生新的见解 将MTB和潜在或非复制的持续MTB分开。 呢