Integration and coordination within complex antibiotic biosynthetic pathways

被称为链霉菌的无害土壤细菌对人类福祉至关重要，因为它们是医生用来治疗传染病的绝大多数抗生素的来源，也为我们提供了许多其他药物，例如，治疗癌症，帮助器官移植患者(免疫抑制剂)。尽管抗生素很重要，但人们对这些细菌如何协调制造这些化合物的机械的所有部件的活动知之甚少。最近的发现表明，抗生素本身和抗生素途径中的中间化合物控制着关键调节因子(称为“转录因子”)的活动，这些调节因子切换这些有用细菌的遗传机制，以协调和整合抗生素的生产。这项工作的目的是找出这些调节剂在分子水平上是如何发挥作用的，它们的活动是如何受到控制的，以及这是如何协调和整合抗生素的合成的。我们将在一个模型系统中对一种名为西莫环酮的抗生素进行这些实验，这种抗生素尚未用于人类医学。然而，由于有强有力的证据表明，我们正在研究的信号机制在生产抗生素的链霉菌中广泛存在，我们的结果可能允许制药公司基于知识提高人类药物中使用的具有商业重要性的抗生素的产量，从而有可能使它们更便宜，更广泛地获得。

The harmless soil bacteria called streptomycetes are vital to human welfare because they are the source of the vast majority of antibiotics used by doctors to cure infectious diseases, as well as providing us with numerous other medicines used, for example, to treat cancer, and to help organ transplant patients (immunosuppressants). Despite the importance of antibiotics, relatively little is understood about how these bacteria coordinate the activities of all the components of the machinery that make these compounds. Recent discoveries have revealed that the antibiotics themselves and intermediate compounds in the antibiotic pathways control the activities of key regulators (called 'transcription factors') that switch the genetic machinery of these useful bacteria to coordinate and integrate the production of antibiotics. The aim of this work is to find out exactly how these regulators work at the molecular level, how their activities are controlled, and how this serves to coordinate and integrate the synthesis of the antibiotics. We will perform these experiments in a model system on an antibiotic called simocyclinone, which is not yet used in human medicine. However, since there is strong evidence that the signalling mechanisms we are studying are widespread in antibiotic-producing streptomycetes, our results might allow pharmaceutical companies to make knowledge-based improvements in the yield of commercially important antibiotics that are used in human medicine, potentially making them less expensive and more widely available.