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Chemical Studies in Bacterial Cell Biology

细菌细胞生物学的化学研究

基本信息

批准号：
7916235
负责人：
Jared Thomas Shaw
金额：
$ 37.31万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-28 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916235
关键词：
Antibiotics Bacteria Bacteria FtsZ protein Bacterial Infections Binding Binding Sites Biological Factors Cell Cycle Cell division Cellular biology Chemicals Complex Cytokinesis DNA Damage Development Disease Escherichia coli Generations Goals Infection Knowledge Label Lead Light Malignant Neoplasms Medicine Molecular Probes Mutate Mycobacterium tuberculosis NMR Spectroscopy Nature Organic Synthesis Organism Parents Peptides Pharmaceutical Preparations Predisposition Process Prokaryotic Cells Proteins Proteomics Research Resistance Resistance development Route SOS Response Screening procedure Structure Synthesis Chemistry Techniques Testing Therapeutic Time Tubulin X-Ray Crystallography analog base chemical synthesis combat computational chemistry design fighting inhibitor/antagonist insight methicillin resistant Staphylococcus aureus novel therapeutics pathogen polymerization research study resistant strain response skeletal small molecule therapeutic development weapons

项目摘要

Project Summary This application describes 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 the 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. Finally, we will use chemical synthesis and new proteomic techniques to elucidate the target of a compound that halts bacterial cell division without acting on FtsZ. This compound may target one of the other fourteen proteins required for cell division, and this would be the first small molecule inhibitor of one of these proteins. 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

项目摘要本申请描述的实验将阐明细菌细胞周期，并阐明在这一过程可能会成为小分子的靶点，以治愈对当前抗生素具有耐药性的感染。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。尽管许多天然产品和其他小分子有效地靶向微管蛋白，导致治疗治愈癌症，针对细菌细胞周期和阻止抗药性感染的能力尚未完全实现探索过了。我们将开发几种以FtsZ为靶标的天然产物的高效合成，我们将使用核磁共振光谱以辨别这些分子如何与FtsZ相互作用。有了这个洞察力，我们将使用计算化学解释导致结合的分子相互作用以及如何设计更多强大的分子。我们还将利用X射线结晶学提供的信息来设计蛋白质- 模仿小分子，可以扰乱细菌细胞分裂，并可能阻止细菌对 DNA损伤，这可能使有机体更容易受到当前抗生素的影响。最后，我们将使用化学合成和蛋白质组学新技术用于阐明一种抑制细菌的化合物的靶标不作用于FtsZ的细胞分裂。这种化合物可能针对其他14种蛋白质中的一种，这些蛋白质是细胞分裂，这将是这些蛋白质之一的第一个小分子抑制剂。这项拟议的研究将揭示细菌细胞周期中的新潜在靶点，可能使新的将开发用于对抗耐药感染的药物。许多由细菌引起的疾病，如“葡萄球菌” 由耐甲氧西林金黄色葡萄球菌(MRSA)引起的感染，不再能用电流治愈因为细菌已经产生了抗药性。我们的研究将使我们了解到细菌分裂和繁殖，使这个可能不会突变和产生抗药性的基本过程像其他过程一样快，可以成为新药的靶点