Mycobacterium Tuberculosis Cell Wall Assembly

结核分枝杆菌细胞壁组装

• 批准号: 9089894
• 负责人: Mary Jackson
• 金额: $ 22.65万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089894
• 关键词: Actins; Address; Anabolism; Anti-Bacterial Agents; Antibiotics; Bacillus (bacterium); Bacillus subtilis; Bacteria; Biochemical; Biological Assay; Cell Wall; Cell division; Cells; Chemistry; Collaborations; Colorado; Complex; Contracts; Corynebacterium glutamicum; Development; Enzymes; Family; Future; Gene Cluster; Genes; Genetic; Genome; Genus Mycobacterium; Gram-Positive Bacteria; Growth; Health; Homologous Gene; In Vitro; Incidence; Individual; Institutes; Japan; Knock-out; Knowledge; Ligase; Link; Maps; Mediating; Molecular; Multi-Drug Resistance; Muramidase; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; N-acetylglucopyranosylamine; National Institute of Allergy and Infectious Disease; Parents; Pathway interactions; Peptidoglycan; Phenotype; Physiological; Physiological Processes; Physiology; Play; Predisposition; Proteins; Recombinants; Resistance; Role; Shapes; Site; Staphylococcus aureus; Structure; Teichoic Acids; Testing; Therapeutic; Therapeutic Studies; Tokyo; Transferase; Universities; Validation; Virulence; arabinogalactan; base; cell assembly; cell envelope; design; in vitro Assay; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; insight; knock-down; lipoteichoic acid; macromolecule; microbial; mutant; mycobacterial; novel; novel strategies; pathogen; permissiveness; programs; research study; resistant strain; retinal rods; scaffold; screening; translocase; tuberculosis drugs

 DESCRIPTION (provided by applicant): The cell envelope of Mycobacterium tuberculosis (Mtb) is the basis of many of the physiological and pathogenic features of this bacterial pathogen and the site of susceptibility and resistance to many anti- tuberculosis drugs. In spite of being Gram-positive bacteria, mycobacteria are unique in having a cell wall devoid of (lipo)teichoic acids and instead containing a heteropolysaccharide known as the arabinogalactan (AG) covalently attached to peptidoglycan (PG). To this date, the cell wall ligase(s) responsible for the covalent attachment of these two macromolecules has/have defied definition. Despite the fundamental structural differences that exist between AG and wall teichoic acids (WTA), the structure of the unit linking AG to PG in mycobacteria shares similarities with the linker involved in the covalent attachment of WTA to PG in many Gram-positive bacteria. Enzymes of the widespread LytR-Cps2A-Psr (LCP) family were recently identified as the likely ligases mediating WTA-PG attachment in Bacillus subtilis and Staphylococcus aureus. We identified three LCP-like proteins in the genome of Mtb H37Rv, one of them mapping to an AG biosynthetic gene cluster. We here propose to use a combination of genetic and biochemical approaches to determine whether these three LCP homologs are the long sought mycobacterial cell wall ligases and to define their therapeutic potential. In particula, we will test whether two novel antibacterial compounds, caprazamycin B and CPZEN-45, products of a collaboration with the Institute of Microbial Chemistry (BIKAKEN, Tokyo, Japan) that inhibit mechanistically similar enzymes in mycobacterial cell wall assembly (MraY and WecA, respectively) may represent promising scaffolds for the future development of inhibitors targeting the assembly of the mycobacterial cell wall. Similar to the situation with WTA ligases, i is likely that the ligase(s) of Mtb interact(s) with other wall proteins to coordinate cell wall synthesis with cell elongation and cell division. The characterization of Mtb's ligase(s) therefore also represents an important first step toward the elucidation of this key aspect of the physiology of mycobacteria and the future design of innovative therapeutic strategies aimed at targeting cell elongation and division.

 描述（由适用提供）：结核分枝杆菌（MTB）的细胞膜是该细菌病原体的许多物理和致病特征的基础，以及对许多抗结核药物的易感性和耐药性的位置。尽管是革兰氏阳性细菌，但分枝杆菌在没有（脂肪）teichoic酸的细胞壁方面是独一无二的，而是含有称为阿拉伯氏菌（Arabinogalactan（AG）的杂多糖，共同附着于辣椒（PG）。到目前为止，负责这两个大分子的共价附着的细胞壁连接酶具有/定义定义。尽管Ag和Wall Teichoic Acid（WTA）之间存在根本的结构差异，但在分枝杆菌中将Ag与PG联系起来的单位结构与与许多革兰氏阳性细菌中WTA与PG共同附着的连接器相似。最近将宽度Lytr-CPS2A-PSR（LCP）家族的酶鉴定为介导WTA-PG附着的枯草芽孢杆菌和金黄色葡萄球菌中WTA-PG附着的可能性连接酶。我们在MTB H37RV的基因组中鉴定了三种LCP样蛋白，其中一个映射到Ag生物合成基因簇。我们在这里建议使用遗传和生化方法的组合来确定这三种LCP同源物是否是长期寻求的分枝杆菌细胞壁连接酶并定义其治疗潜力。部分，我们将测试与微生物化学研究所（Bikaken，日本东京，日本东京）合作的两种新型抗菌化合物B和CPZEN-45是否能否抑制机械性相似的酶，这些酶在Mimacterial Cell壁组装中的旨在抑制机械酶（MRAY和WECA）的发展可能会占有一致（MRAY和WECA）的发展可能会导致未来的发展。分枝杆菌细胞壁。与WTA连接酶的情况类似，我很可能MTB的连接酶与其他壁蛋白相互作用，以将细胞壁合成与细胞伸长和细胞分裂进行协调。因此，MTB连接酶的特征 这也代表了阐明生理关键方面的重要第一步 分枝杆菌和创新治疗策略的未来设计旨在针对细胞伸长和分裂。