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

包括细菌和真菌在内的微生物在环境中无处不在。虽然少数微生物在引起疾病中起作用，但大多数微生物是无害的，其中许多微生物实际上产生对人类有用的药物和化学物质。青霉素就是一个很好的例子，它是由一种真菌产生的，在人类和动物医学中被用作有效的抗生素。其他化合物包括抗癌药物、通过抑制免疫系统而允许器官移植的药物和抗胆固醇药物。许多微生物还能产生对农业非常重要的化合物，这些化合物可以用作杀虫剂、除草剂和杀菌剂。据估计，如果没有这些，目前世界粮食生产力将损失约40%。随着世界人口的增长和气候变化的影响，有效的粮食生产和粮食安全将变得更加重要，这些天然化合物的作用将进一步增强。青霉素在20世纪40年代开始使用，在大约半个世纪的研究中，新发现的天然产物源源不断。然而，随着越来越多的化合物被发现，传统的方法开始失败，因为现有的方法一直在寻找相同的已知化合物。这导致公司尝试其他途径来提供用于药物和农用化学品的新化合物——然而，完全合成的化合物还没有被证明像天然产品那样成功。在过去的十年里，学术研究（大部分由英国生物科学委员会资助，但也是一项国际努力）使人们认识到，大多数微生物都有能力产生比观察到的多得多的化合物——到目前为止，可能只收集了特定生物体潜力的10%。基因组测序揭示了已知生物的生物合成潜力是巨大的，新的生物不断被发现。如果已知生物体中90%未使用的基因能够被激活，那么就会有大量的新化合物用于药物和农用化学品的测试——如果一种通用技术能够利用所有尚未发现的微生物，这种流动可能会增加到洪水。在基因组测序工作的同时，在了解微生物合成次生代谢物的基因、酶和化学方面也取得了巨大进展。这使得微生物中负责合成次级代谢物的途径可以被设计成产生更多的化合物。廉价的全基因组测序和设计微生物途径的能力的融合支撑了这项研究计划。该项目将由6个合作伙伴合作：华威大学的查理斯小组，微生物基因组分析专家；剑桥大学利德利小组，细菌聚酮生物合成专家；曼彻斯特的米克尔菲尔德集团是细菌肽生产方面的专家；布里斯托尔Cox组真菌生物合成专家；先正达（Syngenta）和Biotica，这两家对次生代谢物感兴趣的英国公司。我们将获得已知产生农用化学有用化合物的细菌和真菌的基因组序列。我们将找到负责生产这些化合物的基因，并重组和改造它们，以制造更多的这些化合物，然后建立相关化合物库进行测试。我们将与国际农化公司先正达（Syngenta）的合作伙伴共同开发这些新除草剂、杀虫剂和杀菌剂，而生物技术公司Biotica的合作伙伴将专注于开发用于人类医学的化合物。总的来说，我们的目标是开发一种平台技术，可以利用微生物的潜力来生产用于农业和医学的有用化合物。我们还将广泛传播我们的成果，并开展外联活动，以提高公众对工业生物技术以及基因工程和微生物学在确保未来粮食安全方面的作用的认识。

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.