Assembly of the mycobacterial cell wall

分枝杆菌细胞壁的组装

• 批准号: 8296659
• 负责人: Martin S. Pavelka
• 金额: $ 37.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296659
• 关键词: Acetylglucosamine; Acids; Adult; Alanine; Anabolism; Anaerobiosis; Antibiotics; Appearance; Bacteria; Biochemical; Biological Assay; Biology; Cell Survival; Cell Wall; Cells; Cessation of life; Characteristics; Chimeric Proteins; Complement; Complex; Data; Defect; Development; Diaminopimelic Acid; Drug resistance in tuberculosis; Enzymes; Escherichia coli; Genes; Genus Mycobacterium; Goals; Growth; HIV; Healthcare Systems; Individual; Infectious Agent; Lead; Messenger RNA; Molecular; Monobactams; Morphology; Multi-Drug Resistance; Muramic Acid; Muramidase; Mycobacterium Infections; Mycobacterium tuberculosis; Organism; Pathway interactions; Peptides; Peptidoglycan; Phase; Physiology; Play; Polysaccharides; Post-Translational Protein Processing; Predisposition; Public Health; Recombinants; Reporter; Role; Shapes; Starvation; Structure; Testing; Tuberculosis; cell envelope; crosslink; drug development; enzyme activity; mutant; mycobacterial; novel; peptide L

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis, the causative agent of tuberculosis, is the leading cause of adult death by an infectious organism. Two outstanding characteristics of this organism are its complex cell envelope the biosynthesis of which is the target of several antibiotics, and its ability to persist in latently infected individuals. Major goals of the anti-mycobacterial drug development field include the identification of pathways that are essential for cell envelope biosynthesis and understanding the molecular mechanisms involved in the establishment of persistence. In this regard, one essential biosynthetic pathway that has been overlooked in this field is peptidoglycan (PGN) assembly. The PGN is an essential component of the cell envelope of virtually all bacteria, providing both shape and structural integrity to the cell. Mycobacterial PGN polysaccharide is composed of N-acylmuramic acid and N-acetylglucosamine with peptides (L-alanyl (or glycyl)-D-iso-glutaminyl-meso-diaminopimelyl-D-alanyl-D- alanine) attached to the muramic acid moieties. Peptide cross-links occur between meso-diaminopimelic acid (DAP) residues and either D-alanine or other DAP residues. The mycobacterial PGN is highly crosslinked with 70-80% of the peptides cross-linked and one-third to one-half of the cross-links represented by the DAP-DAP variety. In most other bacteria, DAP-DAP cross-links usually represent only a few percent of the total number of cross-links, suggesting an important role for these cross-links in mycobacterial physiology. The biosynthesis of these unusual cross-links and their function are unknown. It is thought that the enzymes responsible for DAP-DAP cross-links are insensitive to inhibition by R-lactam antibiotics and thus represent a novel class of enzymes to target for drug development. Furthermore, these linkages may be important for cell survival under long-term starvation conditions. However, the pathway for DAP-DAP linkage formation has not been described for any bacterial species. We propose that DAP-DAP linkages are essential for mycobacterial physiology and have a role in stationary phase survival. The formation of these cross-links may also be an important mechanism contributing to the establishment of persistence in tuberculosis latency. The overall goal of this proposal is to better understand cell wall assembly in mycobacteria with a focus on the biosynthesis and significance of DAP-DAP cross-links. Understanding the biology of these cross-links could lead to the development of new antibiotics for the management of latent tuberculosis, which would have a significant impact upon public health. Project Narrative The overall goal of this proposal is to better understand cell wall assembly in mycobacteria with a focus on the biosynthesis and significance of DAP-DAP cross-links. Understanding the biology of these cross-links could lead to the development of new antibiotics for the management of latent tuberculosis, which would have a significant impact upon public health.

描述（由申请人提供）：结核分枝杆菌是结核病的病原体，是传染性生物体导致成人死亡的主要原因。该生物体的两个突出特征是其复杂的细胞包膜（其生物合成是多种抗生素的目标）以及其在潜伏感染个体中持续存在的能力。抗分枝杆菌药物开发领域的主要目标包括识别细胞被膜生物合成所必需的途径以及了解建立持久性所涉及的分子机制。在这方面，该领域被忽视的一个重要的生物合成途径是肽聚糖（PGN）组装。 PGN 是几乎所有细菌细胞膜的重要组成部分，为细胞提供形状和结构完整性。分枝杆菌PGN多糖由N-酰基胞壁酸和N-乙酰葡糖胺以及连接到胞壁酸部分的肽（L-丙氨酰（或甘氨酰）-D-异-谷氨酰胺基-内消旋-二氨基庚二基-D-丙氨酰-D-丙氨酸）组成。肽交联发生在内消旋二氨基庚二酸 (DAP) 残基与 D-丙氨酸或其他 DAP 残基之间。分枝杆菌 PGN 是高度交联的，其中 70-80% 的肽是交联的，而 DAP-DAP 品种则有三分之一到二分之一的交联。在大多数其他细菌中，DAP-DAP 交联通常仅占交联总数的百分之几，这表明这些交联在分枝杆菌生理学中发挥着重要作用。这些不寻常的交联的生物合成及其功能尚不清楚。据认为，负责 DAP-DAP 交联的酶对 R-内酰胺抗生素的抑制不敏感，因此代表了一类新的药物开发目标酶。此外，这些连接对于细胞在长期饥饿条件下的存活可能很重要。然而，尚未描述任何细菌物种的 DAP-DAP 连接形成途径。我们认为 DAP-DAP 连接对于分枝杆菌生理学至关重要，并且在稳定期存活中发挥作用。这些交联的形成也可能是有助于建立结核潜伏期持久性的重要机制。该提案的总体目标是更好地了解分枝杆菌中的细胞壁组装，重点关注 DAP-DAP 交联的生物合成和意义。了解这些交联的生物学可能会导致开发用于治疗潜伏性结核病的新抗生素，这将对公众健康产生重大影响。项目叙述该提案的总体目标是更好地了解分枝杆菌中的细胞壁组装，重点是 DAP-DAP 交联的生物合成和重要性。了解这些交联的生物学可能会导致开发用于治疗潜伏性结核病的新抗生素，这将对公众健康产生重大影响。