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: 10053297
• 负责人: Georgiana E. Purdy
• 金额: $ 48.16万
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053297
• 关键词: Amino Acids; Antibiotics; Apoproteins; Bacteria; Binding; Binding Sites; Biogenesis; Biosynthetic Proteins; Carbon; Cause of Death; Cell Wall; Cells; Chronic; Communicable Diseases; Consensus; Crystallization; DNA Binding; DNA Structure; DNA-Protein Interaction; DNase-I Footprinting; Data; Diglycerides; Docking; EMSA; Esters; Fatty Acids; Gene Expression; Gene Expression Regulation; 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; in silico; 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. !

项目总结 尽管有抗生素可用于抗击结核病，但它仍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，因为它能存活下来。 在免疫细胞内，并有效地建立和维持潜在的结核病感染。因此，理解 建立或维持休眠的基本机制可以为结核病的新战略提供信息 治疗学。 分枝杆菌膜蛋白大蛋白(MMPL)是细胞壁脂类转运蛋白。沿着 对于它们的辅助分枝杆菌膜蛋白小蛋白(MMPs)，这些转运蛋白是至关重要的 分枝杆菌生理学和发病机制的参与者。MmpL3是必不可少的；MmpL4、MmpL5、MmpL7、 MmpL8、MmpL10和MmpL11对结核分枝杆菌的毒力有贡献。MmpL3和MmpL11相关蛋白 运输霉菌酸脂是我们特别感兴趣的。MmpL3转运海藻糖 单菌酯，是分枝杆菌复制和存活所必需的。我们发现MmpL11转运 单链霉菌基二酰甘油和一种霉酚酸酯蜡。这些是脂类的种类，有时 被称为“储存脂”，在体外与休眠细菌有关，并在肉芽肿中积累 结核病患者的比例。因此，MmpL11似乎在一种临床相关但知之甚少的 结核分枝杆菌的发病机制。 虽然在识别MMPL底物方面取得了重大进展，但MMPL蛋白的调节 在不同环境条件下的表达及其在细胞壁重塑中的作用尚未被探讨。 拟议中的研究将描述控制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。我们的初步数据显示 脂肪酸直接调节这些独特的转录因子的活性。这提出了一种模式，在这种模式下，结核分枝杆菌 可以直接评估和响应脂肪酸中间体、代谢状态和营养可获得性的控制 MMPL和MMPs基因调控。通过定义MMPL调节的分子机制 转运蛋白和确定它们的调节，我们将产生新的洞察力之间的过渡积极 将结核分枝杆菌和潜伏的或非复制的永久性结核分枝杆菌分开。 好了！

项目成果

M. tuberculosis AlkX Encoded by rv3249c Regulates a Conserved Alkane Hydroxylase System That Is Important for Replication in Macrophages and Biofilm Formation.

• DOI: 10.1128/spectrum.01969-22
• 发表时间: 2022-08-31
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Stokas, Haley;Rhodes, Heather L.;Simmons, Marit B.;Zhang, Richard;Wright, Catherine C.;Purdya, Georgiana E.
• 通讯作者: Purdya, Georgiana E.

Modulation of the M. tuberculosis cell envelope between replicating and non-replicating persistent bacteria.

• DOI: 10.1016/j.tube.2020.102007
• 发表时间: 2020-12
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Stokas H;Rhodes HL;Purdy GE
• 通讯作者: Purdy GE