Rational engineering of antibiotic production

“链霉菌”细菌表现出复杂的“次级”或非必要新陈代谢，产生被称为“天然产物”的小分子。作为这一过程的一部分，链霉菌产生化疗药物、抗真菌药物、用于防止移植排斥反应的免疫抑制剂、除草剂、抗蠕虫药物，以及最值得注意的是目前临床和农业使用的大多数抗生素。新的链霉菌很容易从土壤中分离出来，但它们的次生代谢物在实验室条件下会产生微量：许多根本检测不到。对次生代谢的研究为我们提供了一系列基因，如果过度表达，可能会极大地增加次生代谢。我们的目标是利用这些基因来生产抗生素生产的“通用激活剂”，可以用来最大限度地提高任何链霉菌的产量。与JNE生物技术公司合作，我们将开发这种资源，用于提高已知药物的生产和发现新药。我们的短期目标是：1.在天蓝色链霉菌和灰链霉菌中鉴定出尽可能多的能刺激抗生素产量增加的基因；2.找到扩大链霉素和壮观霉素产量的方法，最终扩大链霉菌产生的其他抗生素、化疗药物和抗寄生虫药物。从长远来看，我们的目标是将这些工具应用于无特征的链霉菌，以确定能够抑制/杀死感染微生物、寄生虫和肿瘤细胞的新药物。这项工作将通过增加我们对抗生素生产的了解来加强链霉菌的研究领域。这项工作给加拿大带来的好处将包括对研究生和博士后研究员进行复杂的重组dNA和质谱学技术方面的培训。此外，通过提高我们生产已知抗生素和发现新的次生代谢物的能力，我们将加强加拿大的生物技术，并促进当地生物技术公司(JNE Biotech Inc.)的发展。这将增加汉密尔顿制药部门的就业人数。

The "Streptomyces" bacteria exhibit a complex "secondary" or non-essential metabolism, producing small molecules called "natural products". As part of this process, the streptomycetes produce chemotherapeutic agents, anti-fungal drugs, immune suppressants used to prevent transplant rejection, herbicides, anti-helminthic drugs, and most notably the majority of the antibiotics in current clinical and agricultural use. New species of Streptomyces are easy to isolate from the soil but their secondary metabolites are produced in minute quantities under laboratory conditions: many cannot be detected at all. Research into secondary metabolism has provided us with a list of genes that, if over-expressed, could dramatically increase secondary metabolism. Our goal is to exploit these genes to produce "universal activators" of antibiotic production that can be used to maximize output in any streptomycete. In partnership with JNE Biotech Inc. we will develop this resource for use in the enhanced production of known drugs and the discovery of new drugs. Our short term goals are to 1. identify as many of the genes in the species S. coelicolor and S. griseus that can stimulate increased antibiotic production and 2. find ways of amplifying production of streptomycin and spectinomycin, and eventually other antibiotics, chemotherapeutic agents and anti-parasitic drugs produced by streptomycetes. Over the longer term we aim to apply these tools in uncharacterised streptomycetes to identify new agents capable of inhibiting/killing infectious microbes, parasites and tumour cells. This work will strengthen the Streptomyces research field by increasing our understanding antibiotic production. Benefits to Canada from this work will include the training of graduate students and postdoctoral fellows in sophisticated recombinant DN A and mass spectrometry technology. Furthermore, by enhancing our ability to produce known antibiotics and discover new secondary metabolites, we will strengthen biotechnology in Canada and facilitate the growth of a local biotechnology company (JNE Biotech Inc.). This will result in increased employment in the pharmaceutical sector in Hamilton.