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.