Bacterial Division and the Dynamics of the Z-ring

描述(申请人提供)：对药物治疗产生抗药性的致病微生物是一个日益严重的公共卫生问题。结核病、疟疾和耳朵感染只是传统抗生素药物难以治疗的疾病的几个例子。最近发现的具有定形功能的细菌细胞骨架为抗菌治疗提供了新的分子靶点。事实上，现在积累的结果表明，细菌含有类似肌动蛋白和微管蛋白的蛋白质，尽管还没有发现细胞骨架马达蛋白的类似物。原核生物细胞骨架的一个主要功能是细胞分裂(胞质分裂)。特别是，原核蛋白FtsZ是分裂环(Z环)的主要成分。该环是动态维护的。在分裂周期结束时，细胞环收缩，将细胞分离成子细胞。使用经过实验验证的计算方法，我们解决了Z环动力学中的三个核心问题： 1)Z环在体内是如何形成的？2)需要多大的力才能在中点收缩大肠杆菌细胞？3)Z环收缩的机制是什么？它是如何在没有分子马达的情况下产生力的？为了回答这些问题，我们提出了将FtsZ纤维的弹性性质与FtsZ的水解化学相结合的定量模型。模型需要输入参数，这些参数是从活体细胞测量中获得的。Z形环装配和动力学的定量理论模型将直接在实验中得到验证。Z环收缩是大多数细菌中常见的分裂机制。这种已揭示的收缩机制可能会导致针对病原菌分裂周期的新型抗生素药物的开发。

DESCRIPTION (provided by applicant): Disease-causing microbes that have become resistant to drug therapy are an increasing public health problem. Tuberculosis, malaria, and ear infections are just a few examples of the diseases that have become difficult to treat with traditional antibiotic drugs. The recent discovery of a bacterial cytoskeleton with shape-defining function provides new molecular targets for anti-bacterial treatments. Indeed, cumulating results now suggest that bacteria contain proteins that are similar to actin and tubulin, although no cytoskeletal motor protein analogs have been found. A primary function of the prokaryotic cytoskeleton is in cell division (cytokinesis). In particular, the prokaryotic protein FtsZ is the major component of the division ring (Z-ring). The ring is dynamically maintained. At the end of the division cycle, the ring contracts to separate the cell into daughter cells. Using a computational approach validated by experiments, we address 3 central questions in Z-ring dynamics: 1) How does the Z-ring form in vivo? 2) How much force is needed to constrict E. coli cells at mid-point? 3) What is the mechanism of Z-ring contraction and how does it generate force without molecular motors? To answer these questions, we propose quantitative models that combine the elastic properties of the FtsZ filaments with the hydrolysis chemistry of FtsZ. The models require input parameters which are obtained from in vivo living-cell measurements. Quantitative theoretical models of the Z-ring assembly and dynamics will be directly tested experimentally. Z-ring contraction is a common division mechanism found in most bacteria. The revealed contraction mechanism could lead to the development of novel antibiotic drugs that target the division cycle of pathogenic bacteria.