Within the area of microbial natural products chemistry, there is a huge capacity for natural products production. Yet natural products biosynthetic machinery is not evenly distributed across the microbial world. Our laboratory is interested in the development of new strategies and techniques for the isolation and exploration of priority classes of microorganisms from nature. From the porpoise microbiome to the wonderful world of Burkholderia chemistry, we are exploring the fascinating world of microbial chemistry. To achieve this we are creating selective isolation methods for priority genera, developing sampling campaigns for organisms from niche environments, and building libraries of isolates and natural products extracts for high-throughput screening.
Although many natural product structures have been reported over the past 100 years, it is still remarkably difficult to accurately describe the chemical constitution of natural products extracts. Yet if we were able to accomplish this challenge, the resulting knowledge about natural product constitution and distribution would fundamentally alter many of the aspects of modern natural products science. Our group is developing tools to address two outstanding challenges in this area.
For complex natural products extracts it is still difficult to determine an accurate picture of how many unique compounds are present in the sample, or what the physical characteristics (NMR, MS, UV, logP etc) of these compounds are. Using a combination of MS and NMR approaches we are developing new tools for the untargeted characterization of natural products mixtures. The goal of this effort is to create a clear picture of constitution that can be extended to the library scale.
While determining chemical constitution is important, on its own this provides little information about the identities of the detected components. We are also interested in developing tools for automated compound identification that will rapidly and accurately annotate known compounds in any mixture. This work is integrated with our ongoing natural products database project, the Natural Products Atlas.
Natural Products Discovery
The central objective of our research program is to discover natural products with unique and valuable biological properties. Although not limited to a specific disease area, these applications include antibacterials, antiparasitics, and new leads for orphan diseases. We aim to use the technologies that the laboratory has developed in metabolomics, high-throughput screening and informatics to create platforms that will correctly select compounds with the highest development potential from among the thousands of candidates present in any extract library. Using our in-house natural products libraries from around the world we are well positioned to explore the wealth of structural diversity present in nature for functionally important lead compounds.
In addition, we are also interested in applying what we have learned about the chemical space occupied by natural products to design new strategies for structural diversification of natural products libraries. Using a combination of synthetic modification of native natural products extracts and targeted design of novel scaffolds for de novo synthesis, we are building non-natural product libraries for screening and lead development.
High Throughput Screening
Our lab has a strong interest in the development of new screening platforms and modalities for natural products research. These screening platforms are related by our focus on multi-parametric screening methods. Multi-parametric approaches provide detailed biological characterization of the effect of compound treatment on cell development. These data can in turn be used to predict modes of action for bioactive extracts directly from primary screening data. Using the facilities at SFU's new Centre for High-Throughput Chemical Biology ( HTCB ) we are creating new image-based and organism panel-based screening systems that are revealing new insights into the roles that natural products play in modulating biological space.
Mode of Action Determination
To fully exploit the value of compounds with unique biological properties, it is important to understand the mechanism(s) by which they impart this activity. Our laboratory is interested in employing a range of tools and methodologies in the area of chemical biology in order to explore the biological roles of these compounds. These approaches range from compound derivatiztion and chemical probe generation to mass spectrometric and screening-based strategies for mechanistic characterization of these unique compounds.
Many of the tools and platforms developed by the group generate large and complex datasets. To derive highest value from these data we use a range of informatic approaches for data analysis. These range from the creation of new tools to integrate biological and chemical data on natural product libraries for de novo activity predictions, to the development of algorithms to automatically identify journal articles describing natural products discovery, which we use in the Natural Products Atlas project. Development of these tools gives us control over all aspects of the data processing and analysis pipeline, and provides a flexible framework from which we can ask a wide array of questions focused on natural products chemistry. You don't have to be a computer scientist to join our group, but knowing even a little bit will certainly help!
The Natural Products Atlas
The Natural Products Atlas ( www.npatlas.org) is an open access public project to create a universal database containing all published microbial natural products. The long-term goal of this project is to include compounds from both the primary and patent literature, and to include key compound data such as structure, names and synonyms, producing organisms, instances of total synthesis etc. We also aim to link this database to other public databases such as MIBiG and GNPS that contain related information such as biosynthetic gene clusters and MS2 spectra for known compounds.
This project is supported by a large group of volunteers who have helped with article curation and data analysis. For a full list of all contributors please visit the Atlas site.