Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor
Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor
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DOI：
10.1021/cb300340j
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Shaw, Jared T.
中科院分区：
文献类型：
--
作者：
Anderson, David E.;Kim, Michelle B.;Shaw, Jared T.
ZFtsZ 是一种鸟苷三磷酸酶 (GTPase)，可介导细菌的胞质分裂。 FtsZ 在结构上与真核微管蛋白同源，并以类似的头尾方式聚合。真核细胞中微管蛋白功能的研究极大地受益于特异性和有效的小分子抑制剂，包括秋水仙碱和紫杉醇。尽管已报道了许多 FtsZ 小分子抑制剂，但没有一种成为调节细菌细胞分裂的普遍有用的探针。为了建立有用且可靠的 FtsZ 小分子抑制剂，对已报道的 FtsZ 抑制剂进行了广泛的生化交叉比较。其中一些分子，包括酚类天然产物，是非选择性抑制剂，其活性似乎来自微观胶体或聚集体的形成。其他化合物，包括天然产物 viriditoxin 和药物开发候选者 PC190723，使用本工作中的方案或在已公布的条件下，没有表现出对 GTPase 活性的抑制。在所研究的化合物中，只有 zantrin Z3 表现出良好的抑制水平，在破坏小分子聚集体的条件下保持活性，并为探索构效关系 (SAR) 提供了平台。初步 SAR 研究已发现该结构的两个侧链有轻微修改，可调节 zantrin Z3 的抑制活性。总的来说，这些研究将有助于未来的研究重点是建立 FtsZ 探针，以填补秋水仙碱和紫杉醇在微管蛋白研究中的作用。
ZFtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin's function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for Modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross comparison of reported FtsZ, inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to;derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity Using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two side chains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively, these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.