Targeting cell division: Small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality
Targeting cell division: Small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality
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DOI：
10.1073/pnas.0404439101
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发表时间：
2004-08-10
影响因子：
11.1
通讯作者：
RayChaudhuri, D
中科院分区：
文献类型：
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作者：
Margalit, DN;Romberg, L;RayChaudhuri, D
FtsZ是真核细胞微管蛋白的祖先同源物，是一种GTPase，在原核细胞中组装成细胞动力学环结构，对细胞分裂至关重要。与微管蛋白类似，纯化的FtsZ在GTP存在下聚合成动态的原丝；聚合物组装伴随着GTP的水解。我们使用高通量的基于蛋白质的化学筛选来识别靶向FtsZ组装依赖的GTP酶活性的小分子。在这里，我们报告了五个结构不同的化合物，称为Zantrins，它们通过破坏FtsZ原丝的稳定性或通过增加侧向结合诱导微丝的超稳定性来抑制FtsZ GTP酶。这两类FtsZ抑制剂分别让人想起抗微管蛋白药物秋水仙碱和紫杉醇。我们还发现，Zantrins扰乱了大肠杆菌细胞中FtsZ环的组装，并对肉汤培养中的多种细菌造成了致死，表明FtsZ拮抗剂可能成为开发新的广谱抗菌剂的化学先导。我们的结果说明了小分子化学探针在研究FtsZ聚合动力学方面的应用以及FtsZ作为一种新的治疗靶点的可行性。
FtsZ, the ancestral homolog of eukaryotic tubulins, is a GTPase that assembles into a cytokinetic ring structure essential for cell division in prokaryotic cells. Similar to tubulin, purified FtsZ polymerizes into dynamic protofilaments in the presence of GTP; polymer assembly is accompanied by GTP hydrolysis. We used a high-throughput protein-based chemical screen to identify small molecules that target assembly-dependent GTPase activity of FtsZ. Here, we report the identification of five structurally diverse compounds, named Zantrins, which inhibit FtsZ GTPase either by destabilizing the FtsZ protofilaments or by inducing filament hyperstability through increased lateral association. These two classes of FtsZ inhibitors are reminiscent of the antitubulin drugs colchicine and Taxol, respectively. We also show that Zantrins perturb FtsZ ring assembly in Escherichia coli cells and cause lethality to a variety of bacteria in broth cultures, indicating that FtsZ antagonists may serve as chemical leads for the development of new broad-spectrum antibacterial agents. Our results illustrate the utility of small-molecule chemical probes to study FtsZ polymerization dynamics and the feasibility of FtsZ as a novel therapeutic target.