Chemical Studies in Bacterial Cell Biology

描述（由申请人提供）：本申请描述了将阐明细菌细胞周期的实验，并阐明了小分子靶向这一过程的方法，以治疗对当前抗生素具有耐药性的感染。细菌细胞周期的核心是一种叫做FtsZ的蛋白质，它的结构与哺乳动物的微管蛋白相似。尽管许多天然产物和其他小分子有效地靶向微管蛋白，导致治疗癌症的疗法，但靶向细菌细胞周期和阻止耐药感染的能力尚未得到充分探索。我们将开发几种FtsZ靶向天然产物的有效合成，我们将使用核磁共振波谱来辨别这些分子如何与FtsZ相互作用。有了这一见解，我们将使用计算化学来解释导致结合的分子相互作用以及如何设计更有效的分子。我们还将利用x射线晶体学提供的信息来设计模拟蛋白质的小分子，这些小分子可以破坏细菌的细胞分裂，并可能阻止细菌对DNA损伤的反应，这可能使生物体更容易受到当前抗生素的影响。

DESCRIPTION (provided by applicant): This application described experiments that will shed light on the bacterial cell cycle and elucidate ways in which this process might be targeted by small molecules to cure infections resistant to current antibiotics. Central to bacterial cell cycle is a protein called FtsZ, which is similar in structure to mammalian tubulin. Although many natural products and other small molecules target tubulin effectively, resulting in therapies for curing cancer, the ability to target the bacterial cell cycle and halt resistant infections has not been fully explored. We will develop efficient syntheses of several FtsZ-targeting natural products and we will use NMR spectroscopy to discern how these molecules interact with FtsZ. With this insight, we will then use computational chemistry to interpret the molecular interactions that result in binding and how to design more potent molecules. We will also use information provided by X-ray crystallography in the design of protein-mimicking small molecules that can disrupt bacterial cell division and possibly halt the bacterial response to DNA damage, which could render the organism more susceptible to current antibiotics.