A Synthetic Biology Approach for the Total Biosynthesis of Semi-Synthetic Antibiotics
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Natural products are molecules typically produced by plants and microorganisms that have been widely exploited for pharmaceutical and other applications. Often, these molecules nature provides do not have the required properties for use as therapeutic agents and further multi-step synthetic (chemical) transformations are required to produce a final optimised drug molecule. In this project, we are developing new enzymes which can be introduced into a host microorganism to produce the optimised drug molecule in a single-step fermentation process. Such a process will obviate the need for any additional synthetic transformations, which will reduce the environmental damage caused by typical chemical processes. Moreover, a single-step fermentation process will be more cost-effective, than existing synthetic processes, which will enable the cheaper provision of essential medicines.
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
This project brings together four academic labs, and a key industrial partner, with a vision to fundamentally change the way that semi-synthetic antibiotics are manufactured by utilising synthetic biology to transform their manufacture into a single-step total biosynthesis.
Realisation of the goals outlined in this project will then engage industry more widely with this new technology, leading to the total biosynthetic manufacture of a range of other products of commercial and societal importance. The methods developed throughout this project will also address key environmental issues, by providing more environmentally benign and sustainable methods for the biomanufacturing of pharmaceuticals, agrochemicals, and other products from renewable resources, via fermentation.
Realisation of the goals outlined in this project will then engage industry more widely with this new technology, leading to the total biosynthetic manufacture of a range of other products of commercial and societal importance. The methods developed throughout this project will also address key environmental issues, by providing more environmentally benign and sustainable methods for the biomanufacturing of pharmaceuticals, agrochemicals, and other products from renewable resources, via fermentation.
Publications
Winn M
(2021)
Discovery, characterization and engineering of ligases for amide synthesis.
in Nature
Thong WL
(2021)
Gene editing enables rapid engineering of complex antibiotic assembly lines.
in Nature communications
Rowlinson M
(2022)
Reference Module in Chemistry, Molecular Sciences and Chemical Engineering
Gomez-Escribano JP
(2021)
Genome editing reveals that pSCL4 is required for chromosome linearity in Streptomyces clavuligerus.
in Microbial genomics
Bozhüyük KA
(2019)
Engineering enzymatic assembly lines to produce new antibiotics.
in Current opinion in microbiology
Bering L
(2022)
New reaction pathways by integrating chemo- and biocatalysis
in Trends in Chemistry
Description | An enzymatic pathway towards antibiotics has been discovered |
Exploitation Route | These enzymes may find use in industry or by other academics |
Sectors | Chemicals Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
URL | https://research.manchester.ac.uk/en/persons/jason.micklefield |
Description | 10th AGRI-net International conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | 10th AGRI-net International conference at Syngenta's Jealott's Hill Research site, Feb 2023 |
Year(s) Of Engagement Activity | 2023 |
Description | Applied Biocatalysis Summit Philadelphia USA |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | International research presentation held online November 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | BBSRC's Institute Assessment Exercise (IAE) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | BBSRC's Institute Assessment Exercise (IAE) Panel Member (2022). |
Year(s) Of Engagement Activity | 2022 |
Description | BIOTRANS 2023 La Rocehelle |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Attended Biotrans 2023 https://www.biotrans2023.com/ |
Year(s) Of Engagement Activity | 2023 |
Description | BioNoW - 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | BioNoW - 2022 BioInfect Conference, Alderley Park, 9 Mar 2022 |
Year(s) Of Engagement Activity | 2022 |
Description | Chemistry and Biology of Natural Product XI |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | NPRONET Postgraduate event |
Year(s) Of Engagement Activity | 2017 |
Description | Chemistry and Biology of Natural Products XII |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Event for postgraduate students and PDRAs to discuss the latest natural products research |
Year(s) Of Engagement Activity | 2018 |
Description | Directing Biosynthesis Edinburgh |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at Directing Biosynthesis Edinburgh |
Year(s) Of Engagement Activity | 2022 |
Description | Directing Biosynthesis VI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Directing Biosynthesis VI online 12-13 April, 2021 (Plenary, Bader Award Lecture) |
Year(s) Of Engagement Activity | 2021 |
Description | East China University of Science and Technology, Shanghai, China, May 6, 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at a conference discussing research from the Micklefield lab |
Year(s) Of Engagement Activity | 2019 |
Description | European Society of Applied Biocatalysis (ESAB), Biocatalytic Total Synthesis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | European Society of Applied Biocatalysis (ESAB), Biocatalytic Total Synthesis, May 2022 |
Year(s) Of Engagement Activity | 2022 |
Description | Flavins & Flavoproteins |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Flavins & Flavoproteins, Graz, Austria, 5-9 Sept 2021. |
Year(s) Of Engagement Activity | 2021 |
Description | GSK invited lecture 2018, 21 March, 2018, Stevenage. |
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 | 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 | Postgraduate students |
Results and Impact | Presentation at a conference discussing research from the Micklefield lab |
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 | 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 about our research |
Year(s) Of Engagement Activity | 2017 |
Description | John Innes Centre (JIC), Norwich |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | John Innes Centre (JIC), Norwich, Feb 2023 presentation to whole department |
Year(s) Of Engagement Activity | 2023 |
Description | Lecture at Imperial College, London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Imperial College to the Chemistry department covering a variety of material from the research group |
Year(s) Of Engagement Activity | 2023 |
Description | Lecture at University of Bristol |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at the University of Bristol to the Chemistry department covering a variety of material from the research group |
Year(s) Of Engagement Activity | 2023 |
Description | Lecture at the University of Greenwich |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at Greenwich University to the Chemistry department covering a variety of material from the research group |
Year(s) Of Engagement Activity | 2023 |
Description | MIB Seminar November 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Presentation to postgraduates within the Manchester Institute of Biotechnology |
Year(s) Of Engagement Activity | 2022 |
Description | Merck (MSD) USA (host) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Merck (MSD) USA (host), online lecture to all Merck sites across the world 7 April, 2021 |
Year(s) Of Engagement Activity | 2021 |
Description | Museum Outreach day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Describing our research to the general public |
Year(s) Of Engagement Activity | 2017 |
Description | NPRONET Community meeting 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | 2 NPRONET event to bring whole community together |
Year(s) Of Engagement Activity | 2017 |
Description | NPRONET Community meeting 2018 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | NPRONET event to bring the whole community together and discuss natural product research |
Year(s) Of Engagement Activity | 2018 |
Description | Open day for 6 form and college students |
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 | Open day with for local sixth form and college students |
Year(s) Of Engagement Activity | 2018 |
Description | Open day for 6 form and college students |
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 | Open day with for local sixth form and college students |
Year(s) Of Engagement Activity | 2017 |
Description | Peking University, Beijing, China, 2019, May 9, 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Presentation at a seminar discussing research from the Micklefield lab |
Year(s) Of Engagement Activity | 2019 |
Description | Plenary lecture at Biocatalysis and Biotransformations (BioTrans 2019), July 7-11, 2019, in Groningen, |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at a conference discussing research from the Micklefield lab |
Year(s) Of Engagement Activity | 2019 |
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 | RSC Organic Ireland Regional Meeting, Trinity College Dublin |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | RSC Organic Ireland Regional Meeting held at Trinity College Dublin |
Year(s) Of Engagement Activity | 2023 |
Description | Royal Society of Chemistry Horizon Prize Video |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Royal Society of Chemistry Horizon Prize Video filmed in January 2024 and release on Youtube describing research in the Micklefield lab. |
Year(s) Of Engagement Activity | 2024 |
Description | SIAS (Spectroscopy in a suitcase) |
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. A portable Bruker IR machine is used for analysis and to explain how it works students in Yr11 or higher |
Year(s) Of Engagement Activity | 2018 |
Description | Shandong University, Qingdao, China, May 8, 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at a meeting discussing research from the Micklefield lab |
Year(s) Of Engagement Activity | 2019 |
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 | Postgraduate students |
Results and Impact | Presentation at a conference discussing research from the Micklefield lab |
Year(s) Of Engagement Activity | 2018 |
Description | Synthetic Biology of Natural Products Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Presentation at Synthetic Biology of Natural Products Conference |
Year(s) Of Engagement Activity | 2022 |
Description | University of Nottingham, Chemistry Department |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | University of Nottingham, Chemistry Department, June 2022 |
Year(s) Of Engagement Activity | 2022 |
Description | • Solids Liquids and Gases Show |
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 series of demonstrations involving dry ice (carbon dioxide), oxygen and liquid nitrogen. |
Year(s) Of Engagement Activity | 2017,2018 |