New Synthetic biology tools for controlling gene expression

目前临床使用的48%的药物和80%以上的抗生素都是以天然产物为基础开发的。然而，在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，并且通常需要进一步的合成转化来产生最终的优化化合物。将天然产物转化为更有效的衍生物所需的额外合成步骤增加了成本，并且通常涉及昂贵且污染的试剂和溶剂。因此，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更清洁和更具竞争力的途径，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学技术，天然产物生物工程和酶导向进化的最新进展，开发一种基于发酵的单一工艺，可以提供重要的抗生素，避免了任何额外的合成转化的需要。作为世界领先的制药公司之一，葛兰素史克公司对该项目非常感兴趣，因此博士生将受益于在葛兰素史克公司的近距离接触和实习时间，以及显著提高的津贴。在曼彻斯特和GSK的培训将包括：蛋白质工程、定向进化、酶表征和分析。在这个项目中也会有发展分子生物学和微生物学技能的空间。最近相关研究的例子：通过修饰腺苷酸化结构域特异性将非天然氨基酸引入非核糖体肽抗生素。J.瑟尔韦，R.刘易斯，L.纳恩斯，M.阿尔纳基布，M.斯泰尔斯，A. W.斯特鲁克，C. P.史密斯，J.米克尔菲尔德。化学。Int。艾德,心血管病。[j] .中国生物医学工程学报，2012,51,7181-7184 (http://dx.doi.org/10.1002/anie.201202043)Engineered)。M.-C。吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强，吴明强。（http://dx.doi.org/10.1099/mic.0.000095）Site-specific RapM 16- o -甲基转移酶的雷帕霉素生物烷基化。B. J. C. Law， A.-W。杨建军，杨建军，杨建军，等。化工科学，2015,6(1):1 -2。（http://dx.doi.org/10.1039/C5SC00164A）Modular不同细菌物种合成遗传控制的核糖开关工具集。C. J.罗宾逊，H. A.文森特，m . C.。吴，P. T.洛，M. S.邓斯坦，D。和J.米克菲尔德J. Am。化学。社会科学学报，2014,36,10615-10624。（http://dx.doi.org/10.1021/ja502873j）Bioengineering用于治疗应用的天然产物生物合成途径。M.-C。吴，B. Law， B. Wilkinson， J. Micklefield Curr。当今。Biotechnol。， 2012, 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)