Marine Bacterial Natural Products: From Discovery to Biosynthesis

细菌天然产物(NPs)是细菌产生的生物活性分子，是治疗药物的宝贵来源。例如，2015年诺贝尔生理学或医学奖承认了两种治疗传染性寄生虫病的纳米粒子的发现，自1980年以来，新的抗菌剂中有70%来自于纳米粒子。去年强调了传染病对人类健康的全球威胁，到2050年，抗菌素耐药性感染有望超过癌症，成为加拿大人的主要死亡原因。因此，我们继续开发抗菌治疗是至关重要的，而大自然仍然是寻找新药物线索的最佳资源之一。许多“低垂的果实”NPs已经被发现；然而，在合适的生长条件下，细菌能够产生比迄今发现的更多数量级的NPs。该计划旨在开发模拟海洋细菌自然栖息地的分子发现的尖端方法，以诱导它们产生许多新的NPs。我们将利用细菌基因组信息与基因编辑技术相结合，激活预测性生物信息学工具优先考虑的特定候选NPs的生产。所有新的NPs都将被研究其生物活性，特别是抗菌特性。我们还将进行生物合成研究，以探索细菌如何从Prodiginine/Tambjamine家族中产生羊毛硫肽NPs和生物活性生物碱。由于多种原因，研究生物合成很重要。首先，了解细菌是如何制造分子的，有助于开发更好的生物信息学预测算法，这是基因组引导NP发现的关键要素。其次，来自NP生物合成的酶是新生物催化剂的极好来源，可用于在温和的条件下进行高水平的立体和区域控制的复杂化学反应，促进药物分子(无论它们是否来自NP)和精细化学品的大规模生产。该计划将在未来5年资助15名HQP的培训，所支持的多元化研究团队将在包括生物技术、医学、制药和环境科学在内的多个领域为加拿大的知识经济做出重要贡献。我们的跨学科计划将侧重于在包容和支持性的环境中为HQP配备技术专业知识和补充项目管理、沟通和协作技能，消除参与障碍。我们的计划将提供实验工具，使药物发现和NP社区的其他人能够探索环境细菌的全部生物合成范围。我们获得的生物合成洞察力也将有助于集体发现工作，并为未来的工程努力奠定基础，以生产造福所有加拿大人的下一代抗菌药物。

Bacterial Natural Products (NPs) are bioactive molecules produced by bacteria that serve as an invaluable source of therapeutics. For example, the 2015 Nobel Prize in Physiology or Medicine recognized the discovery of two NPs that treat infectious parasitic diseases and since 1980 ~70% of new antibacterial agents are derived from NPs. The last year has emphasized the global threat to human health posed by infectious disease, and antimicrobial resistant infections are poised to overtake cancer as a leading cause of death for Canadians by 2050. It is, therefore, critical that we continue to develop antimicrobial treatments, and nature remains one of the best resources for finding novel drug leads. Many of the "low hanging fruit" NPs have already been discovered; however, under the right growth conditions bacteria are able to make orders of magnitude more NPs than have been identified to date. This program seeks to develop cutting edge methods for molecule discovery that mimic the natural habitat of marine bacteria, to induce them into producing many new NPs. We will leverage bacterial genome information in combination with gene editing technology to activate production of specific candidate NPs prioritized by predictive bioinformatic tools. All new NPs will be investigated for their bioactivity, with a particular focus on antimicrobial properties. We will also undertake biosynthetic investigations to probe how bacteria produce lanthipeptide NPs and bioactive alkaloids from the prodiginine/tambjamine family. Investigating biosynthesis is important for multiple reasons. Firstly, understanding how molecules are made by bacteria enables development of better bioinformatic prediction algorithms, a critical element of genome guided NP discovery. Secondly, enzymes from NP biosynthesis are excellent sources of new biocatalysts that can be used to carry out complex chemical reactions with high levels of stereo and regiocontrol under mild conditions, facilitating the large-scale production of drug molecules (whether or not they are NP derived) and fine chemicals. This program will fund the training of 15 HQP over the next 5 years, and the diverse team of researchers supported will be important contributors to the knowledge economy of Canada in several fields including Biotechnology, Medicine, Pharmaceuticals and Environmental Science. Our interdisciplinary program will focus on equipping HQP with technical expertise and complementary project management, communication, and collaboration skills in an inclusive and supportive environment where barriers to participation are removed. Our program will provide experimental tools to enable others in the drug discovery and NP community to probe the full biosynthetic scope of environmental bacteria. The biosynthetic insights we gain will also aid collective discovery efforts and lay the groundwork for future engineering efforts to produce the next generation of antimicrobial drugs benefiting all Canadians.