Unlocking the biomedical potential of microbial symbionts from complex ecosystems

项目总结/文摘

Project summary/abstract New therapeutics are desperately needed for the treatment of diseases with unmet needs, such as emerging infections and immunological diseases. Specialized metabolites (natural products) produced in nature have historically played a critical role in drug discovery, however high rates of rediscovery have resulted in a significant drop in drug candidates. The long-term goal of this proposed research program is to use an ecology-based discovery platform to investigate complex ecosystems, specifically the microbiota of marine egg masses, where evolutionary pressures exist to evolve specialized metabolites that can be leveraged as anti-infective and immunomodulating therapeutics. The success natural products have had in the clinic is due to their evolutionary history, their structures and functions evolved over millions of years of selective pressures to carry out an essential role for the producing organism. For example, many of the antibiotics used in the clinic today are produced by terrestrial microorganisms that use them to vanquish competitors. The microbiomes of marine egg masses provide an intriguing source of potential drug candidates as it has been hypothesized that evolutionary pressure has led to the development of defensive metabolites and these defensive metabolites can be repurposed for the treatment of infections in humans. Our first long term goal is to establish the egg mass microbiota as a host of diverse bacterial symbionts and then using these symbionts to build a natural product fraction library. This fraction library has been screened in a variety of biological assays, with an initial focus on anti-infective and immunomodulating assays, and the natural products components of each fraction are being profiled with innovative metabolomics techniques, nuclear magnetic resonance-based MADByTE and mass spectrometry-based GNPS. Active components will be elucidated, their biosynthetic gene clusters identified, and evaluated in an in vivo rodent model. Our second goal is to leverage the ability of the isolated microbes to produce novel metabolites as studies have revealed that only a fraction (< 25%) of the metabolites are produced under typical laboratory conditions. Using a community-based co-culturing technique and innovative techniques that utilize collected egg masses will allow us to replicate many of the chemical interactions that occur in the ecological environment, which are known play an important role in the regulation of these silent metabolites. Collectively, our proposed research program will broadly impact the field by establishing marine egg masses as a good source of novel natural products. Studying the small molecules produced by these bacterial symbionts will lead to the discovery of novel anti-infective agents and has the potential to repopulate the drug pipeline targeting unmet and increasingly frequent diseases.