Mtb regulators of essential and virulence-associated MmpLs

必需 MmpL 和毒力相关 MmpL 的 Mtb 调节因子

• 批准号: 9106596
• 负责人: Georgiana E. Purdy
• 金额: $ 47.64万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106596
• 关键词: 1,2-diacylglycerol; Algorithms; Antibiotics; Bacteria; Binding; Binding Sites; Carbon; Carrier Proteins; Cause of Death; Cell Wall; Cells; ChIP-seq; Chronic; Communicable Diseases; Computer Simulation; Consensus; DNA; DNA Binding; DNA-Protein Interaction; DNase-I Footprinting; Data; Diglycerides; Docking; Electrophoretic Mobility Shift Assay; Esters; Fatty Acids; Gene Expression; Gene Expression Regulation; Genes; Health; Immune; Immune response; In Vitro; Infection; Ligand Binding; Ligands; Lipids; Maintenance; Membrane Proteins; Metabolic; Microbial Biofilms; Modeling; Molecular; Mycobacterium tuberculosis; Mycolic Acid; Nucleic Acid Regulatory Sequences; Nutrient; Oxidative Stress; Pathogenesis; Patients; Physiology; Play; Protein Export Pathway; Proteins; Regulation; Regulon; Resistance; Role; Site-Directed Mutagenesis; Source; Staging; Stimulus; Stress; Structure; System; Therapeutic; Transcriptional Regulation; Trehalose; Tuberculosis; Virulence; Waxes; Work; clinically relevant; combat; insight; interest; lipid biosynthesis; lipid transport; mycobacterial; mycolate; novel; overexpression; pathogen; protein expression; protein transport; small molecule; transcription factor; tuberculosis granuloma

 DESCRIPTION (provided by applicant): 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 function of 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 some 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.

 描述（由适用提供）：尽管抗生素可用于对抗结核病（TB），但它是由于传染病而导致的死亡原因之一。结核分枝杆菌（MTB）是一种成功的病原体，因为它在免疫核管内存活，并有效地建立和维持潜在的结核病感染。因此，了解休眠的建立或维持的基础机制可以为结核病治疗的新策略提供信息。分枝杆菌膜蛋白大（MMPL）蛋白是专用的细胞壁脂质转运蛋白。这些转运蛋白与它们的辅助分枝杆菌膜蛋白小（MMPS）蛋白相比，是分枝杆菌生理和发病机理中的关键参与者。 MMPL3是必不可少的； MMPL4，MMPL5，MMPL7，MMPL8，MMPL11和MMPL11有助于MTB病毒。我们特别感兴趣的含霉菌酸脂质的相关蛋白MMPL3和MMPL11的功能。 MMPL3运输海藻糖单霉菌酸盐，是分枝杆菌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霉菌酯蜡。这些是脂质的物种，有时被称为“储存脂质”，并且在体外与休眠细菌有关，并在结核病患者的肉芽肿瘤中积聚。因此，MMPL11似乎在MTB发病机理的临床相关但知之甚少的方面中起作用。尽管已经确定了MMPL底物的重大进展，但尚未探索MMPL蛋白表达的调节及其在不同环境条件下细胞壁重塑中的作用。拟议的研究将表征MTB转录调节剂的结构和功能，该调节剂控制着基本和病毒相关的MMPL和MMPS蛋白的表达。我们的初步数据表明脂肪酸直接调节某些转录因子的活性。这表明MTB可以直接评估和响应脂肪酸中间体，代谢状态以及控制MMMPL和MMMPS基因调节的养分。通过定义调节MMPL转运蛋白调节的分子机制并确定其法规，我们将对积极分裂MTB与潜在或不重复的持久MTB之间的过渡产生新的见解。