Chemical Studies in Bacterial Cell Biology

描述(申请人提供)：本申请描述了将阐明细菌细胞周期的实验，并阐明了这一过程可能成为小分子靶标以治愈对当前抗生素耐药的感染的方法。细菌细胞周期的中心是一种名为FtsZ的蛋白质，它在结构上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，从而产生了治疗癌症的方法，但靶向细菌细胞周期和阻止耐药性感染的能力尚未得到充分探索。我们将开发几种以FtsZ为靶标的天然产物的有效合成，并将使用核磁共振光谱来识别这些分子如何与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射线结晶学提供的信息来设计类似蛋白质的小分子，这些小分子可以扰乱细菌细胞分裂，并可能阻止细菌对DNA损伤的反应，这可能会使微生物对目前的抗生素更敏感。 与公共卫生相关：拟议的研究将揭示细菌细胞周期内的新的潜在目标，这些目标可能使开发新的药物来对抗耐药感染。许多由细菌引起的疾病，例如由耐甲氧西林金黄色葡萄球菌(MRSA)引起的“葡萄球菌”感染，已经无法用目前的抗生素治愈，因为细菌已经产生了抗药性。我们的研究将产生关于细菌如何分裂和繁殖的知识，以便这一可能不会像其他过程那样迅速突变和产生耐药性的基本过程可以成为新药的靶点。

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. PUBLIC HEALTH RELEVANCE: The proposed research will reveal new potential targets within that bacterial cell cycle that may enable new medicines to be developed to combat resistant infections. Many diseases caused by bacteria, such as "staph" infections caused by MRSA (methicillin-resistant Staphylococcus aureus), can no longer be cured with current antibiotics because the bacteria have developed resistance. Our research will result in knowledge about how bacteria divide and multiply so that this essential process, which may not mutate and develop resistance as quickly as other processes, can be targeted with new drugs.