Small Molecule Inhibitors of Bacterial Cell Division

细菌细胞分裂的小分子抑制剂

• 批准号: 6943912
• 负责人: DEBABRATA RAYCHAUDHURI
• 金额: $ 26.93万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943912
• 关键词: Francisella tularensis; analog; antibacterial agents; bacterial proteins; bioterrorism /chemical warfare; cell cycle proteins; chemical genetics; cytotoxicity; drug interactions; guanosinetriphosphatases; high throughput technology; phosphatase inhibitor; small molecule

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 GTP 酶，它在细胞分裂部位组装成环状结构，并招募其他必需的分裂蛋白以形成对细菌胞质分裂至关重要的隔膜环。 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、其与微管蛋白的低氨基酸一致性以及其在哺乳动物细胞中的缺失，使其成为有吸引力的广谱抗菌靶点。使用基于 FtsZ 蛋白质和化学遗传的高通量筛选小分子文库，已鉴定出许多导致细胞丝状化和细菌致死的命中。全细胞筛选已经鉴定出两类分子，它们会导致致命的丝状化，无论是否影响 FtsZ 活性，这表明对其他重要但尚未确定的分隔目标的抑制。该项目的目标之一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间隔特异性非 FtsZ 靶点。另一个目标是使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。这项工作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中的细胞分裂的有效治疗先导化合物。