Small Molecule Inhibitors of Bacterial Cell Division

描述(申请人提供)：FtsZ是一种重要的微管蛋白样GTP酶，在细胞分裂部位组装成环结构，并招募其他必要的分裂蛋白形成对细菌胞质分裂至关重要的隔环。FtsZ在细菌界中广泛保守，包括大多数病原体和生物制剂，但在高等真核生物的线粒体中缺失。FtsZ在细菌细胞分裂中的重要性，其广泛的保守性，它与微管蛋白的氨基酸同源性低，以及它在哺乳动物细胞中的缺失，使其成为一个有吸引力的广谱抗菌靶点。使用基于FtsZ蛋白的筛选以及针对小分子文库的化学遗传高通量筛选，已经确定了一些导致细胞丝状化和细菌致死性的命中。全细胞筛选发现了两类分子，它们能在影响FtsZ活性的情况下或不影响FtsZ活性的情况下导致致命的丝状化，这表明其他基本的但尚未确定的分离靶点受到了抑制。该项目的一个目标是使用这些分裂抑制物作为化学工具来研究隔环组装，并识别和验证隔膜特异性的非FtsZ靶点。另一个目标是将这些有前景的抑制剂用作类似物合成和结构-功能关系研究的化学支架。这一努力可能有助于开发针对公共卫生重要细菌病原体和生物制剂中的细胞分裂的有效治疗线索。

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.