New Synthetic biology tools for controlling gene expression

目前，48%的药品和80%以上的临床使用的抗生素都是以天然产品为基础的。然而，自然界中产生的化合物不一定具有药物开发所需的活性或性质，通常需要进一步的合成转化才能产生最终的优化化合物。将天然产物转化为更有效的衍生品所需的额外合成步骤增加了成本，而且往往涉及昂贵且污染环境的试剂和溶剂。因此，一种可以避免额外合成转化的过程将为许多有价值的产品提供一条更清洁、更具竞争力的途径，包括对抗新出现的抗菌素耐药性所需的基本抗生素。该项目将结合新的合成生物技术、天然产品生物工程的最新进展和酶导向的进化，开发一种基于发酵的单一过程，可以提供重要的抗生素，而不需要任何额外的合成转化。世界领先的制药公司之一葛兰素史克对这个项目非常感兴趣，因此，博士生将受益于在葛兰素史克的密切接触和安置时间，以及显著增加的津贴。在曼彻斯特和葛兰素史克的培训将包括：蛋白质工程、定向进化、酶特性和分析。该项目还将有机会发展分子生物学和微生物学方面的技能。最近相关研究的例子通过腺化结构域特异性的修饰将非天然氨基酸引入非核糖体多肽抗生素中。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容化学。内部艾德。利用拉莫拉宁甘露糖基转移酶RAM29合成耐拉西丁脂环肽抗生素的(http://dx.doi.org/10.1002/anie.201202043)Engineered。吴明昌，史明强，罗伯杰，史翠克，纳恩斯，米克尔菲尔德微生物学2015,161,1338-1347。RAPM16-O-甲基转移酶催化雷帕霉素的(http://dx.doi.org/10.1099/mic.0.000095)Site-specific生物烷基化反应B.J.C.Law，A.-W.Strike，M.R.Bennett，B.Wilkinson和J.Micklefield Chemical Science 2015 6,2885-2892。(用于不同细菌物种的合成遗传控制的http://dx.doi.org/10.1039/C5SC00164A)Modular核糖开关工具集。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容化学。SoC。2014年，136,10615-10624。用于治疗应用的(http://dx.doi.org/10.1021/ja502873j)Bioengineering天然产物生物合成途径。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容奥平。Biotechnol，2012年，23,931-940.(http://dx.doi.org/10.1016/j.copbio.2012.03.008)

Natural products have formed the basis for the development of 48% of all pharmaceuticals and over 80% of all antibiotics in clinical use today. However the compounds produced in nature do not necessarily possess the activity or properties required for drug development and further synthetic transformations are often necessary to generate the final optimised compound. The additional synthetic-steps required to transform the natural product into a more effective derivative increases costs and often involves reagents and solvents that are expensive and polluting. Consequently, a process that can circumvent the need for additional synthetic transformations would provide a cleaner and more competitive route to many valuable products including essential antibiotics that are required to combat emerging antimicrobial resistance. This project will combine new synthetic biology technologies, state-of-the art advancements in natural products bioengineering and enzyme directed evolution to develop a single fermentation-based process that can deliver important antibiotics, obviating the need for any additional synthetic transformations. This project is of major interest to GlaxoSmithKline, one of the worlds leading pharmaceutical companies, and the PhD student will therefore benefit from close contact and placement periods at GSK as well as a significantly enhanced stipend. Training in Manchester and at GSK will include: Protein engineering, directed evolution, enzyme characterisation and assays. There will also be scope within the project to develop skills in molecular biology and microbiology. Examples of recent related researchIntroduction of a non-natural amino Acid into a nonribosomal Peptide antibiotic by modification of adenylation domain specificity. J. Thirlway, R. Lewis, L. Nunns, M. Al Nakeeb, M. Styles, A. W. Struck, C. P. Smith, J. Micklefield Angew. Chem. Int. Ed. Engl., 2012, 51, 7181-7184 (http://dx.doi.org/10.1002/anie.201202043)Engineered Biosynthesis of Enduracidin Lipogyclopeptide Antibiotics using the Ramoplanin Mannosyltransferase Ram29. M.-C. Wu, M. Q. Styles, B. J. C. Law, A. W. Struck, L. Nunns and J. Micklefield Microbiology 2015, 161, 1338-1347. (http://dx.doi.org/10.1099/mic.0.000095)Site-specific bioalkylation of Rapamycin by the RapM 16-O-methyltransferase. B. J. C. Law, A.-W. Struck, M. R. Bennett, B. Wilkinsonand J. Micklefield Chemical Science 2015 6, 2885-2892. (http://dx.doi.org/10.1039/C5SC00164A)Modular Riboswitch Toolsets for Synthetic Genetic Control in Diverse Bacterial Species. C. J. Robinson, H. A. Vincent, M.-C. Wu, P. T. Lowe, M. S. Dunstan,D. Leys, and J. Micklefield J. Am. Chem. Soc. 2014, 136, 10615-10624. (http://dx.doi.org/10.1021/ja502873j)Bioengineering natural product biosynthetic pathways for therapeutic applications. M.-C. Wu, B. Law, B. Wilkinson, J. Micklefield Curr. Opin. Biotechnol., 2012, 23, 931-940.(http://dx.doi.org/10.1016/j.copbio.2012.03.008)