A synthetic biology platform for the discovery and commercialization of natural products.

专门的代谢物(也称为天然产物)是由具有强大生物活性的环境微生物制造的自然产生的分子。有些是有益的：青霉素、万古霉素、两性霉素和四环素被用作抗生素来对抗细菌和真菌感染。相反，有些则是有害的。黄曲霉毒素就是一个例子，它是一种潜在的致命毒素，由污染食物的曲霉产生，是肝脏损伤和癌症的病原体。这项建议涉及诺德韦尔实验室和多伦多研究化学品公司共同感兴趣的专门代谢物：黄曲霉毒素和胃泌素。诺德威尔实验室正在开发抗菌素；多伦多研究化学公司需要黄曲霉毒素的来源，以作为便携式黄曲霉毒素检测试剂盒的标准。在这一研究和商业化领域的主要限制是，专门的代谢物往往是由制造它们的微生物产生的非常少量的。分子本身通常太复杂，无法合成，所以这是一个主要的障碍。诺德威尔实验室和多伦多研究化学公司合作的目的是通过开发在非常高的水平上生产这些分子的方法来克服这一障碍。为此，我们将制定策略，优化这些分子的生物合成基因，以便在活细胞中更高水平地表达。我们将把这些优化过的基因改造成可控制基因表达的“底盘”菌株。最后，我们将开发工业化规模的培养条件，以适合我们的研究和商业化需求的规模生产每个分子。这是一个最初的重点：我们将这项关于黄曲霉毒素和胃泌素的工作视为一项试验性努力，在未来几年，我们将建立一个平台，我们可以将其应用于许多其他共同感兴趣的化合物。我们希望这将导致持续的合作。

Specialized metabolites (also known as natural products) are naturally-occurring molecules made by environmental microorganisms that have potent biological activities. Some are beneficial: penicillin, vancomycin, amphoteracin and tetracycline are used as antibiotics to fight bacterial and fungal infections. Conversely, some are harmful. An example is aflatoxin, a potentially fatal toxin produced by food-contaminating Aspergillus species and the causative agent of liver damage and cancer. This proposal concerns specialized metabolites that are of shared interest between the Nodwell laboratory and Toronto Research Chemicals: aflatoxin and pepticinnamin. The Nodwell laboratory is developing pepticinnamin as an anti fungal drug; Toronto Research Chemicals needs a source of aflatoxin to serve as a standard in portable detection kits for aflatoxin. The major limitation in this area of research and commercialization is that the specialized metabolites tend to be produced in very small amounts by the microbes that make them. The molecules themselves are usually too complicated to produce synthetically so this is a major road block. The purpose of this collaborative effort between the Nodwell lab and Toronto Research Chemicals is to overcome this road block by developing methods for producing these molecules at very high levels. To this end we will develop strategies for optimizing the biosynthetic genes for these molecules for higher level expression in living cells. We will engineer these optimized genes into "chassis" strains designed for controlled gene expression. Finally we will develop industrial-scale culture conditions for producing each molecule at a scale appropriate for our research and commercialization needs. This is an initial focus: we regard this work on aflatoxin and pepticinnamin as a trial effort in which we will generate a platform that we can apply to many other compounds of shared mutual interest in the years to come. Our hope is that this will lead to ongoing collaboration.