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.

Publications

10 25 50
 
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 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 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 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 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 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 • 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