Elucidating novel regulatory mechanisms of antimycin-type depsipeptide biosynthesis

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。在能够产生这些化合物的细菌基因中，只有大约十分之一是在实验室中表达的。换句话说，全球制药业是建立在生物化学多样性的10%的基础上的。缺乏关于细菌如何控制这些可能有用的化学物质的生产的知识是药物发现领域面临的最重大挑战之一，这一领域的根本性进展可能导致发现和开发许多针对各种疾病的新疗法。我们已经确定了一种新的调节蛋白（称为“转录因子”），它控制通路中一个基因子集的表达，该通路产生具有抗癌活性的化合物，并治疗神经退行性疾病，阿尔茨海默氏症和帕金森病。用小分子治疗这些与年龄有关的疾病是非常有吸引力的，并且有可能降低死亡率并改善患者的生活质量。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被控制的，以便我们可以设计它们的过量生产。这样做将导致以知识为基础的产量提高，我们采取的方法和我们制造的工具可以同样用于其他潜在药物，可能使它们更便宜，更广泛地使用。

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.