Genome mining of marine bacteria to uncover and interrogate secondary metabolite biosynthetic pathways

海洋细菌基因组挖掘揭示和探究次生代谢物生物合成途径

• 批准号: RGPIN-2015-06078
• 负责人: Ross, Avena
• 金额: $ 2.33万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708191
• 关键词: Genome; mining; marine; bacteria; uncover

I will develop an interdisciplinary research program to identify bioactive compounds from marine bacterial sources and understand the fundamental mechanisms by which they are biosynthesized. This program will provide HQP with the opportunity to engage in several fields including molecular biology, biochemistry, and organic chemistry. By learning about the mechanisms that bacteria use to synthesise complex molecules, scientists can apply the same approaches to engineer bacteria to make new and potentially useful molecules. This has far reaching impacts on large-scale manufacture of complex molecules by fermentation that represents a cost effective and environmentally responsible alternative to total chemical synthesis.  The primary focus of this program is a genus of bacteria called Pseudoalteromonas that has shown promise as a source of interesting biomolecules but is under-investigated to date. In the long term this program will expand to encompass other marine proteobacteria that display biosynthetic potential. A genome-to-molecule approach will be used to identify potentially non-canonical biosynthetic pathways that will then be captured and expressed in a host bacterium to allow molecule discovery and investigation of the biosynthetic enzymes. Initially we will focus on the identification of potentially interesting pathways by analysis of bacterial genome sequences using a process called "Genome Mining". A groundbreaking technology called Transformation-Associated Recombination will be used to capture pathways of interest. This highly innovative technique enables specific and selective capture of target regions of DNA facilitating subsequent expression and genetic manipulation experiments. This approach has very recently been applied to the capture and study of natural product biosynthetic genes by a very small number of laboratories worldwide, including that of my postdoctoral supervisor, Dr. Moore at UCSD. The use of this technique will be critical to the program, and also completely novel in the Canadian scientific community. After this technique is employed to capture the pathways, they will be heterologously expressed in a host bacterium and product molecules will be identified. Using genetic and enzymology approaches, the biosynthetic genes and corresponding enzymes will then be probed. This technique will allow us to uncover novel biosynthetic processes, prepare novel molecules and better understand the remarkable workings of biosynthetic enzymes.  HQP trained within this program will develop strong communication and leadership skills to complement critical thinking and subject expertise. Through research collaborations, research exchanges and conference attendance, HQP will develop global networks that will maximise their capacity to contribute to the Canadian scientific community, both in academia and industry.

我将开发一个跨学科的研究项目，从海洋细菌来源中识别生物活性化合物，并了解它们生物合成的基本机制。该项目将为HQP提供参与多个领域的机会，包括分子生物学、生物化学和有机化学。