Marine Bacterial Natural Products: From Discovery to Biosynthesis

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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.