Small Molecule Inhibitors of Bacterial Cell Division

描述（由申请人提供）： FtsZ是一种必需的微管蛋白样GTP酶，其在细胞分裂位点组装成环状结构，并募集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环。FtsZ在细菌界广泛保守，包括大多数病原体和生物威胁剂，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同一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标。使用基于FtsZ蛋白质以及针对小分子文库的化学遗传学高通量筛选，已经鉴定了许多导致细胞增殖和细菌致死的命中。全细胞筛选已经确定了两类分子，导致致死性抑制或不影响FtsZ活性，这表明抑制其他重要的，但尚未确定的分隔目标。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隔环组装，并识别和验证隔特异性非FtsZ目标。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的合成和结构-功能关系的研究。这一努力可能有助于开发有效的治疗线索，靶向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。

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.