A Synthetic Biology Approach for the Total Biosynthesis of Semi-Synthetic Antibiotics
Lead Research Organisation:
John Innes Centre
Department Name: Molecular Microbiology
Abstract
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Technical Summary
Currently, derivatives of natural products, widely-used as antibiotics, agrochemicals and other valuable compounds, are manufactured using multi-step processes. This project will develop a scalable, cleaner and more competitive single-step process for the manufacture of high value natural product derivatives, including antibiotics. Improved approaches to pathway engineering, utilising advances in DNA assembly and gene editing, will enable the total biosynthesis of the target antibiotics, circumventing the need for additional transformations. We will use directed evolution and structure-guided engineering to generate new biosynthetic enzymes with novel activities to create new pathways to the antibiotics. Additionally, the use of biosensors controlling GFP will aid the selection of the best mutant enzymes and pathways producing the highest levels of antibiotics. Strains will be optimised for the production of target antibiotics by deleting unnecessary genes, while ensuring that precursor supply is maintained when new engineered genes are introduced.
Planned Impact
As described in proposal submitted to IUK.
Publications
Bozhüyük K
(2019)
Engineering enzymatic assembly lines to produce new antibiotics
in Current Opinion in Microbiology
Gomez-Escribano J
(2021)
Genome editing reveals that pSCL4 is required for chromosome linearity in Streptomyces clavuligerus
in Microbial Genomics
Description | A high quality genome sequence assembly, backed up by physical mapping, was generated for the important industrial strain Streptomyces clavuligerus. This information was produced to enable the project and was made available to the wider scientific community and generated a publication. |
Exploitation Route | We maintain our relationship with our industrial partner GSK with whom we will take forward any outcomes that arise. |
Sectors | Chemicals Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Antibiotic total synthesis (BioCatalyst) |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | Intellectual input for assembly line biosynthesis engineering and Streptomyces genetics |
Collaborator Contribution | Knowledge of beta-lactam natural product biosynthesis and production, and genetics of Streptomyces clavuligerus |
Impact | None yet. Multi-disciplinary project involving gentetics, genomics, microbiology and natural products chemistry |
Start Year | 2017 |
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 | Nanjing University of Technology, Nanjing, China, October 16, 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 to academics at Nanjing University of Technology about research in the Micklefield group |
Year(s) Of Engagement Activity | 2018 |
Description | Plenary lecture, Society for Chemical Engineering and Biotechnology (DECHEMA) conference on "Emerging Trends in Natural Product Biotechnology" September 20-21, 2018, at TU Dortmund University, Germany |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation to academics at the BMWZ Symposium 2018 about research in the Micklefield group |
Year(s) Of Engagement Activity | 2018 |
Description | School Science week presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Policymakers/politicians |
Results and Impact | School science week - gave one hour presentations on the role of microbes in bioremediation |
Year(s) Of Engagement Activity | 2019 |
Description | School visit (Cambourne Cambs) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Spent two days presenting a cross curriculum presentation to two classes of Year 6 pupils at a primary school in collaboration with the SAW Trust (http://sawtrust.org/ ). Much debate and discussion about the topics of microbes, antibiotics, ecology and antimicrobial resistance. |
Year(s) Of Engagement Activity | 2018 |
URL | http://sawtrust.org/buy-the-books/saw-antibiotics/ |
Description | School visit (Cambourne Cambs) |
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 | Deliver a Science, Arts and Writing workshop event on the topic 'Antibiotics: what they are and where they come from'. Delivered a one day event, to two Year 6 classes (one each day). The event generated significant discussion, and involved hands on learning. |
Year(s) Of Engagement Activity | 2014,2015,2016,2017,2018,2019,2021,2022,2023,2024 |
URL | https://sawtrust.org/ |
Description | Synthetic Biology Congress, Munich, Germany, October 8-9, 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 | 2014,2018 |