New Synthetic biology tools for controlling gene expression
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
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)
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)
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011208/1 | 01/10/2015 | 31/03/2024 | |||
| 1787418 | Studentship | BB/M011208/1 | 01/10/2016 | 30/09/2020 |
| Description | Chemistry - Nailed it! activity at local shopping centre |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Why do gel nails last longer than normal nail varnish? How can nail polish look holographic? Why use magnets for nail art? The public engaged in hands on activities with our workshop and learn about the chemistry behind different types of nail varnish. We used an every day example of different chemistry to engage the public to talk about Science (held at the Trafford Centre in Manchester). This encourage the public to talk and engage in discussion about Science related topics and about other things we do at the University of Manchester. The impacts I feel arose from this is an increase in public awareness of different research going on but also encouraging the younger but also older generation to pursue an interest in Science in their future. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Engagement in British Science week 2018 |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Presented at a plasmid and transcription/translation themed stand for primary school children. This sparked them to ask questions about science and encouraged them to consider Science in their future. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Engagement in Polymer Day - 5th June 2018 |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Teaching year 10 children (group of 8 each) about polymers, performed experiments such as opening sulphur ring structures (ring opening polymerisation). Polymer-melt processing and other activities with polycaprolactone. Condensation polymerisation with Nylon 6, 10 formation making nylon threads and making slime with PVA and borax. Area: School from Manchester and there were 40 students in total. This workshop allowed the students to speak to students of University about what going to University is like and what their options are. It also encouraged them to ask Science related questions and to perform experiments they wouldn't have been able to perform otherwise. I think a main outcome of this visit was that it increased their enthusiasm about Science and allowed them a taster of Science at University. To help them make an informed decision about their future. |
| Year(s) Of Engagement Activity | 2018 |
| Description | ICBS2018, Vancouver Canada, September 24-27, 2018 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Presentation about research in the Micklefield group |
| Year(s) Of Engagement Activity | 2018 |
| Description | Teachers workshop at the University of Cumbria |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | Assisted at a workshop introducing teachers to Royal Society of Chemistry teaching resources. This sparked questions about teaching practice and potential resources available through RSc to schools. I think the major outcome of this engagement activity is that the teachers left with a surplus of free teaching activities and ideas to aid their teaching of Science to the students. Therefore this had a great impact on the education of the students these teachers would teach. |
| Year(s) Of Engagement Activity | 2018 |
| Description | • MIB Interactive stand for A-level students |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Learning about antibiotics, how they are found, how they work and what we do in the MIB with them. It gave the students an insight into what sort of research we do at the University of manchester and helped inform them so they are able to make decisions about their University choices. The school reported that the students found it very helpful and informative. |
| Year(s) Of Engagement Activity | 2017,2018 |
| Description | • SIAS (Spectroscopy in a suitcase) school visits |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | A paracetamol synthesis followed by analysis (by IR and TLC) workshop. We have a portable Bruker IR machine and explanation of how it works is required to the students Yr11 or higher (we have aids to help them visualise the vibration of the bonds). During this time they may also ask questions about life at university and even potentially what is involved in doing a chemistry degree. Also teaching NMR and working through NMR problems with the children. After the school reported an increased interest in Science and a deeper understanding of the specific topics we covered. Therefore helping them in this topic when it comes to their exams. |
| Year(s) Of Engagement Activity | 2018 |
| Description | • Science Spectacular Museum Outreach day |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Engaged with the public teaching about cell surface glycans and their uses in scientific research which sparked questions and discussion afterwards and increased awareness of the public in the sorts of things we do in the University of Manchester, the public reported increased interest in Science and that they learnt something new |
| Year(s) Of Engagement Activity | 2017 |
| Description | • Solids Liquids and Gases Shows |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | This activity, a series of demonstrations involving dry ice (carbon dioxide), oxygen and liquid nitrogen, is also well-suited to senior primary or junior secondary pupils. As well as turning solids and liquids into gases, we also turn gases into liquids and have lots of fun with balloons, bangs and bottle-rockets. This grabs the attention of learners to drive home issues of pressure, forces and states of matter while injecting plenty of excitement. It is often delivered by trained students, closer in age group to the audience, who can act as role models. The school reports it massively increases the students interest in Science and their engagement in Science classes. |
| Year(s) Of Engagement Activity | 2017,2018 |
| Description | • Speech at Prenton High School for Girls |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Talked about my time at school, what inspired me to do science and what I am doing now. To try to encourage more girls to go into Science. The parents, teachers and students reported that it encouraged them to go into Science and about that it was possible for them to go to University and do a PhD. |
| Year(s) Of Engagement Activity | 2017 |