A Synthetic Biology Approach for the Total Biosynthesis of Semi-Synthetic Antibiotics

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.

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.

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.