Exploiting natural product assembly line genomics and synthetic biology for discovery and optimisation of novel agrochemicals

Microorganisms including bacteria and fungi are everywhere in the environment. Although a few microorganisms have roles in causing disease, most microorganisms are harmless, and many of them actually produce medicines and chemicals useful to man. A good example is penicillin which is produced by a fungus and used as an effective antibiotic in human and animal medicine. Other compounds include anticancer drugs, drugs which allow organ transplants by suppressing the immune system and anticholesterol drugs. Many microbes also produce compounds of huge importance in agriculture which can be used as insecticides, herbicides and fungicides. It is estimated that around 40% of current world food productivity would be lost without these. As the world population grows and as climate change takes hold efficient food production and food security will become more important and the roles of these naturally occurring compounds will increase yet further.
Penicillins came into use during the 1940s, and for around half a century research provided a steady stream of newly discovered natural products. However, traditional approaches began to fail as more and more compounds were discovered because the available methods kept finding the same known compounds. This led companies to try other avenues to provide new compounds for use as medicines and agrochemicals - however fully synthetic compounds have not proven as successful as natural products.
Over the past decade academic research, much funded in the UK by BBSRC, but also an international effort, has led to the understanding that most microbes have the capacity to produce very many more compounds than observed - perhaps only 10% of a given organism's potential has been collected to-date. Genome sequencing has revealed that the biosynthetic potential of known organisms is huge - and new organisms are continually being found. If the 90% of unused genes in just the known organisms could be activated there could be a strong flow of new compounds for testing as medicines and agrochemicals - this flow could be increased to a flood if a generic technology could exploit all the as-yet undiscovered microbes.
In parallel with the genome sequencing efforts huge progress has also been made in understanding the genes, enzymes and chemistry involved in the microbial synthesis of secondary metabolites. This now allows the pathways responsible for the synthesis of secondary metabolites in microbes to be engineered to produce yet more compounds. The confluence of cheap whole genome sequencing and the ability to engineer microbial pathways underpins this research proposal.
The project will be a collaboration between 6 partners: the Challis group at Warwick, expert in microbial genome analysis; the Leadlay group at Cambridge, expert in bacterial polyketide biosynthesis; the Micklefield group in Manchester, expert in bacterial peptide production; the Cox group in Bristol expert in fungal biosynthesis; and Syngenta and Biotica, UK companies with major interest in secondary metabolites. We will obtain the genome sequences of bacteria and fungi known to produce agrochemically useful compounds. We will find the genes responsible for their production and recombine and engineer them to make higher amounts of these compounds, and then libraries of related compounds for testing. We will work with partners in the international agrochemical company Syngenta to develop these as new herbicides, insecticides and fungicides, while partners at the Biotechnology company Biotica will focus on compounds with use in human medicine. Overall we aim to develop a platform technology which can exploit the potential of microbes for the production of useful compounds for use in agriculture and medicine. We will also disseminate our results widely and undertake outreach activities to increase public awareness of industrial biotechnology and the role of genetic engineering and microbiology in ensuring future food security.

This project will exploit a major opportunity which has arisen due to three factors: the dramatic lowering in cost of microbial full genome sequencing; the recent advances in rational engineering of microbial metabolic pathways; and the re-emergence of interest in natural products as new agrochemicals and drugs by international companies. The project will bring together 6 partners: the Challis group at Warwick, expert in genomics-based natural product discovery; the Leadlay group at Cambridge, expert in bacterial polyketide biosynthesis; the Micklefield group in Manchester, expert in bacterial nonribosomal peptide bioengineering; the Cox group in Bristol expert in fungal biosynthesis; and Syngenta and Biotica, UK companies with major interest in secondary metabolites. The collaboration will allow the 6 partners to embark on an ambitious programme to rapidly sequence the genomes of 40 microorganisms with the known ability to produce compounds with potential in the agrochemical arena. New bioinformatic methods will be used to rapidly identify biosynthetic gene clusters and link them to the synthesis of particular compounds. Engineering will then be employed to increase titres and activate 'silent' gene clusters with potential to produce bioactive compounds. Focussed libraries of target compounds will be made by biosynthetic engineering and the libraries used for SAR by Syngenta. Compound activity will then be maximised by a combination of biosynthetic engineering and synthetic chemistry. The partners will also engage in dissemination, training and outreach activities designed to maximise the impact of the project in the academic, industrial and public communities.

Short term: The project will have high impact with the directly involved partners. For the companies involved it will allow them to gain access to and exploit the significant pool of knowledge and experience within the UK academic community in the area of biosynthetic engineering and synthetic biology. In particular this will help give Syngenta a competitive advantage and maintain their significant research and employment base in the UK. It will have a significant impact for the 4 academic groups involved because it will allow them to collaborate and disseminate best practice in complementary areas of research - this is likely to lead to more publications and publications of higher impact and thus help maintain the UK's competitivity in this area. It will help the academic groups focus their efforts on the development of new products and bring knowledge and experience from commerce into the academic arena. This in turn will enable the academic groups to form new and effective collaborations.

Medium term: The research has a good likelihood of leading to the development of new products with utility in the agrochemicals sphere which will underpin improvements in food security internationally. The project will train at least 8 PDRAs and up to 4 students in the area of synthetic biology as applied to industrial biotechnology. These people will form a core of expertise which will benefit both academia and industry.

Long term: The development of a platform technology for the systematic exploitation of microbes for the development of new medicines and agrochemicals will form the basis for the development of new technologies using synthetic biology. For example it is likely that similar methodology will underpin the development of new materials, new fine chemicals and processes, new methods to access biofuels and new methods to access foodstuffs.