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Elucidating novel regulatory mechanisms of antimycin-type depsipeptide biosynthesis

阐明抗霉素型缩酚肽生物合成的新调控机制

基本信息

批准号：
BB/N007980/1
负责人：
Ryan Seipke
金额：
$ 43.39万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN007980%2F1
关键词：
Elucidating novel regulatory mechanisms antimycin

项目摘要

Soil bacteria, namely streptomycetes, produce more than half of all drugs used in human medicine, ranging from antibiotics to cure infectious disease as well as drugs to treat cancer and enable organ transplantation. Only about one-tenth of the bacterial genes that enable the production of these compounds are expressed in the laboratory. In other words, the global pharmaceutical industry is based on ~10% of the biochemical diversity it could be. A lack of knowledge as to how bacteria control the production of these potentially useful chemicals is one of the most significant challenges faced by the field of drug discovery and fundamental advances in this area could result in the discovery and development of a multitude of new therapeutics for a wide range of diseases. We have identified a novel regulatory protein (called a 'transcription factor') that controls the expression of a subset of genes in the pathway that makes compounds with promising activity as anticancer agents and treatments for the neurodegenerative conditions, Alzheimer's and Parkinson's diseases. Treating these age-related diseases with a small molecule is very attractive and has the potential to decrease the mortality and improve the quality of life of patients. Our ultimate goal is elucidate other regulators of this pathway and understand in detail how production of these molecules is controlled so that we may engineer their overproduction. Doing so will result in knowledge-based improvements in yield and the approaches we take and tools we make could be used in the same with for other potential drugs, possibly making them less expensive and more widely available.

土壤细菌，即链霉菌，生产人类医学中使用的所有药物的一半以上，从治疗传染病的抗生素到治疗癌症和器官移植的药物。只有大约十分之一的细菌基因能够在实验室中表达这些化合物。换句话说，全球制药业的基础是大约10%的生物化学多样性。缺乏关于细菌如何控制这些潜在有用的化学物质的产生的知识是药物发现领域面临的最重大挑战之一，并且该领域的基本进展可能导致发现和开发用于广泛疾病的多种新疗法。我们已经确定了一种新的调节蛋白（称为“转录因子”），它控制通路中一组基因的表达，使化合物具有作为抗癌剂和治疗神经退行性疾病，阿尔茨海默病和帕金森病的有希望的活性。用小分子治疗这些与年龄相关的疾病是非常有吸引力的，并且具有降低死亡率和改善患者生活质量的潜力。我们的最终目标是阐明这一途径的其他调节因子，并详细了解这些分子的产生是如何控制的，以便我们可以设计它们的过度生产。这样做将导致基于知识的产量提高，我们采取的方法和工具可以用于其他潜在药物，可能使它们更便宜，更广泛地获得。