NATURAL PRODUCTS DISCOVERY AND BIOENGINEERING NETWORK (NPRONET)

Many microorganisms and plants produce molecules that possess a broad spectrum of biological activities. These natural products, also known as secondary metabolites, have been used in the development of many blockbuster drugs including anticancer, immunosuppressive, and cholesterol-lowering agents. Furthermore the majority of antibiotics in clinical use are derived from natural products. Despite this the development of new natural product based pharmaceuticals has declined in recent years. In particular the supply of new antibiotics has diminished to the extent that antibiotic-resistant pathogens (superbugs) are now widely recognised as a major global health threat. Natural products are also used in agriculture as herbicides, pesticides, and fungicides to increase crop yields which can help feed the growing population. In addition natural products are used in other commercial products including perfumes and flavourings.
Recent advances in gene sequence technologies have enabled the entire genome sequence of many secondary metabolite producing microorganisms and plants to be determined. This has revealed many new clusters of genes that encode the necessary enzymes required to assemble natural products. However many of these gene clusters are either silent or do not give rise to detectable quantities of compound under normal laboratory conditions. Consequently nature has the potential to produce many more secondary metabolites than was ever envisaged. A central goal of NPRONET will be to devise methods for activating these silent or low yielding gene clusters. For example the unproductive gene clusters can be transferred and expressed in an alternative host strain which has been genetically modified to enhance production of secondary metabolites. This will require the development of new computational and experimental technologies that can be deployed to rapidly engineer host strains and manipulate large gene clusters. In some cases new regulatory elements will need to be designed which can be used to control expression of gene clusters. Ultimately this will enable new secondary metabolites to be produced in quantities sufficient for commercial development.
Many natural products are highly complex molecules that are difficult to synthesise or modify using traditional chemistry. Consequently it is often difficult to generate structural variants, or second generation molecules, with enhanced biological activity or improved physical properties for subsequent commercial applications. NPRONET will therefore develop new bioengineering methods and tools which will enable rapid structural diversification and optimisation of the most promising natural product molecules. To do this NPRONET will establish a detailed understanding of the mechanisms by which some of the most promising natural products are assembled. This knowledge will then be used to re-program a specific gene cluster to enable incorporation of alternative precursors, the re-ordering of the assembly or the introduction of different tailoring modifications (methylation, glycosylation, hydroxylases, halogenation etc.)
To tackle these major industrial and societal grand challenges NPRONET will need to be multidisciplinary, bringing together chemists, biologists, computational scientists, engineers and others who have interests in natural products discovery and bioengineering. This will include research leaders from both academia and industry (small and large) as well as other end-user groups. Through a series of network events, proof-of-concept funding and other activities NPRONET will facilitate new collaborative partnerships to explore new ways of working together that will accelerate the natural product discovery and bioengineering process.

Secondary metabolites produced by microorganisms and plants have inspired the development of leading pharmaceuticals including anticancer, immunosuppressive, cholesterol-lowering agents as well as most of the antibiotics in clinical use today. Natural products are also used in agriculture as crop-protection agents to increased crop yields which can help feed the growing population. With the advent of next-generation DNA sequencing technologies the number of microbial and plant genome sequences has increased dramatically revealing a vast array of new biosynthetic gene clusters.
NPRONET will integrate genomics data and utilise systems/synthetic biology tools in order to discover new natural products and to guide the bioengineering of natural product scaffolds for therapeutic, agricultural and other applications including more efficient and diverse routes for the production of fine and commodity chemicals. It is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. A key goal of NPRONET will be to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. In addition, NPRONET will utilise the expanding mechanistic and structural knowledge of biosynthetic enzymes to develop new strategies for re-programming biosynthetic pathways. Taking advantage of technologies from synthetic biology it is envisaged that new bioengineering approaches can be developed to optimise yields and increase the structural diversity of natural product scaffolds, delivering focused libraries of key modified products with improved biological properties.
To address these major challenges NPRONET will bring together academic and industrial experts from chemistry, biology, computational science and engineering, estabishing new collaborations through network events and proof-of-concept funding.

The industrial members of NPRONET come from across the pharmaceutical, agrochemical, fine chemicals and other biotechnology sectors including SMEs (Novacta, Cantab Anti-infectives, Demuris, Hypha, Saffron 2020, EntreChem SL, Isomerase and Biosyntha) as well as large multinational companies (GSK, Syngenta, Novartis, Pfizer, Dr Reddy's, Croda). These companies will be the principal industrial beneficiaries, as they seek to develop natural products as potential pharmaceutical agents, agrochemicals and other high value chemical products. In addition, we will proceed to attract other industrial members both in the UK and overseas, as the network develops. The development of further links with overseas companies will be aided by our international advisory board, whose remit will include exploring mechanisms by which NPRONET research can impact the global natural products research and commercial development effort. There are also other industries that could potentially benefit from the cross-cutting systems and synthetic biology tools and technologies that NPRONET will develop. These include companies who are interested in metabolic engineering approaches to generate biofuels and other lower value, high volume platform chemicals (Shell, BP, Du Pont, DOW, Amyris). Similarly exploration of new biosynthetic pathways, emerging from genome sequence data, is likely to uncover many new enzymes. Some of the enzymes that NPRONET discover, could be developed as commercial biocatalysts which can be used to transform cheap feeds stocks into higher value products and intermediates. This would be of interest to some of the NPRONET industrial members, but also to a range of additional companies including (Lonza, DSM, BASF, Novozymes, Ingenza, Johnson Matthey) who are increasingly looking to exploit biocatalysis.
To enable the industrial members and other industrial groups to gain maximum benefit, NPRONET will organise a series of events. These events will include workshops to disseminate cutting edge research, exchange best practice and explore new ways of working together including the sharing of technologies between the academic and industrial research groups. In addition NPRONET will organise sand-pits based on focused themes, which will be led by research leaders, with a view to identifying synergies and potential collaborative partnerships between industrial and academic groups. NPRONET will also provide proof-of-concept funding which will enable groupings identified in sand-pits to develop their collaboration through one year joint projects. These proof-of-concept projects are intended to generate the necessary preliminary results that are required for the construction of larger grant applications to external bodies. Industrial groups will help steer the strategic direction of the network and will benefit from being involved in all our events. Industrial collaboration in proof-of-concept projects will be crucial and should provide the companies involved freedom to explore new research areas, with academic groups, which could also open up new commercial opportunities.