Small Molecule Inhibitors of Bacterial Cell Division

细菌细胞分裂的小分子抑制剂

• 批准号: 7281275
• 负责人: DEBABRATA RAYCHAUDHURI
• 金额: $ 27.07万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281275
• 关键词: Affect; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic-resistant organism; Antibiotics; Bacillus anthracis; Bacillus subtilis; Bacteria; Bacterial Model; Biochemical; Categories; Cell Proliferation; Cell division; Cells; Cessation of life; Chemicals; Class; Clinical; Cytokinesis; Development; Drug Prescriptions; Enzymes; Escherichia coli; Eukaryota; Eukaryotic Cell; Francisella tularensis; Genetic Screening; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; In Vitro; Lead; Life; Link; Mammalian Cell; Mitochondria; Molecular Probes; Mycobacterium tuberculosis; Numbers; Organism; Orthologous Gene; Poison; Proteins; Public Health; Range; Recruitment Activity; Research Personnel; Resistance; Site; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Testing; Therapeutic; Tubulin; Variant; Virulent; analog; base; biothreat; cellular targeting; chemical genetics; cytotoxicity; depolymerization; genetic analysis; high throughput screening; inhibitor/antagonist; killings; pathogen; polymerization; programs; scaffold; small molecule; small molecule libraries; tool

DESCRIPTION (provided by applicant): FtsZ is an essential tubulin-like GTPase that assembles into a ring structure at the site of cell division and recruits other essential division proteins to form the septal ring critical for bacterial cytokinesis. FtsZ is widely conserved in the Bacterial kingdom, including most pathogens and biothreat agents, but is absent in the mitochondria of higher eukaryotes. The essentiality of FtsZ in bacterial cell division, its widespread conservation, its low amino acid identity with tubulin, and its absence in mammalian cells make it an attractive broad-spectrum antibacterial target. Using FtsZ protein-based as well as chemical genetic high throughput screens against small molecule libraries, a number of hits have been identified that cause cell filamentation and bacterial lethality. The whole-cell screens have identified two classes of molecules that cause lethal filamentation with or without affecting FtsZ activity, suggesting inhibition of other essential but as yet unidentified septation targets. One goal of the project is to use these division inhibitors as chemical tools to study septal ring assembly and to identify and validate septation-specific non-FtsZ targets. Another goal is to use the promising inhibitors as chemical scaffolds for analog synthesis and structure-function relationship studies. This effort may aid the development of potent therapeutic leads that target cell division in bacterial pathogens of public health importance and in biothreat agents.

描述（由申请人提供）：FtsZ是一种必需的微管蛋白样GTPase，在细胞分裂位点组装成环状结构，并招募其他必需的分裂蛋白形成对细菌细胞分裂至关重要的间隔环。FtsZ在细菌界广泛保守，包括大多数病原体和生物威胁因子，但在高等真核生物的线粒体中不存在。FtsZ在细菌细胞分裂中的重要性，其广泛的保守性，与微管蛋白的低氨基酸同源性，以及在哺乳动物细胞中的不存在，使其成为一个有吸引力的广谱抗菌靶点。利用基于FtsZ蛋白的以及针对小分子文库的化学遗传高通量筛选，已经确定了许多导致细胞丝化和细菌致死的命中。全细胞筛选已经确定了两类分子，这些分子在影响或不影响FtsZ活性的情况下导致致命的丝化，这表明抑制了其他重要但尚未确定的分离目标。该项目的一个目标是使用这些分裂抑制剂作为化学工具来研究间隔环组装，并识别和验证分隔特异性的非ftsz靶标。另一个目标是利用有前途的抑制剂作为化学支架进行类似物合成和结构-功能关系研究。这一努力可能有助于开发针对具有公共卫生重要性的细菌病原体和生物威胁剂的细胞分裂的有效治疗线索。