Integration and coordination within complex antibiotic biosynthetic pathways

复杂抗生素生物合成途径中的整合和协调

• 批准号: BB/I002197/1
• 负责人: Mark Buttner
• 金额: $ 58.94万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI002197%2F1
• 关键词: Integration; coordination; within; complex; antibiotic

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.

被称为链霉菌的无害土壤细菌对人类福祉至关重要，因为它们是医生用于治疗传染病的绝大多数抗生素的来源，并为我们提供了许多其他药物，例如用于治疗癌症和帮助器官移植患者（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器的所有组件的活动知之甚少。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，这些调节因子转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工作的，它们的活性是如何被控制的，以及它们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Simocyclone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传导机制在产生抗生素的链霉菌中广泛存在，我们的研究结果可能使制药公司能够在人类医学中使用的商业重要抗生素的产量方面进行基于知识的改进，从而可能使它们更便宜，更广泛地获得。

项目成果

The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding.

• DOI: 10.1093/nar/gkr640
• 发表时间: 2011-11
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Le TB;Schumacher MA;Lawson DM;Brennan RG;Buttner MJ
• 通讯作者: Buttner MJ

SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone.

• DOI: 10.1016/j.jmb.2015.03.019
• 发表时间: 2015-06-19
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Schaefer, Martin;Le, Tung B. K.;Hearnshaw, Stephen J.;Maxwell, Anthony;Challis, Gregory L.;Wilkinson, Barrie;Buttner, Mark J.
• 通讯作者: Buttner, Mark J.

Response regulator heterodimer formation controls a key stage in Streptomyces development.

• DOI: 10.1371/journal.pgen.1004554
• 发表时间: 2014-08
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Al-Bassam MM;Bibb MJ;Bush MJ;Chandra G;Buttner MJ
• 通讯作者: Buttner MJ

Phage p1-derived artificial chromosomes facilitate heterologous expression of the FK506 gene cluster.

• DOI: 10.1371/journal.pone.0069319
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jones AC;Gust B;Kulik A;Heide L;Buttner MJ;Bibb MJ
• 通讯作者: Bibb MJ

Fluorescence Time-lapse Imaging of the Complete S. venezuelae Life Cycle Using a Microfluidic Device.

• DOI: 10.3791/53863
• 发表时间: 2016-02-28
• 期刊: Journal of visualized experiments : JoVE
• 作者: Schlimpert S;Flärdh K;Buttner J
• 通讯作者: Buttner J