New Synthetic biology tools for controlling gene expression

点击翻译按钮获取中文摘要

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)