Capturing evolved small molecule natural product chemical space

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Natural small chemicals, natural products, exhibit a wide spectrum of activity with significant industrial and medicinal value. Within their natural context these molecules have been evolved as a form of communication between cells and to assist the life of the organisms that produce them. Their evolved status is evident in the selectivity to their bio-molecular targets and demonstrated impact on cells. Biosynthetic machinery leading to natural products of different categories (e.g. terpenes, polyketides, nonribosomal peptides) are now well appreciated and their codes have been cracked such that the connection between genetic instruction and end product small molecules is appreciated. The advent of genomic sequencing of natural product sources have opened up a large cache of new natural products that await discovery and evaluation for their industrial and pharmaceutical use. The purpose of the proposed research program will be to design and implement powerful new tools and strategies to enable the rapid connection of genomic information to small molecule natural products. The propose research program will seek to develop powerful strategies to selectively identify and capture these evolved natural products a reality for testing. Genomic sequencing of proven antibiotic producers and numerous poorly studied microorganisms has produced a deep view of their metabolic capability. These genomically-envisioned cohort of microbial natural products, or what can be referred to as ‘unknown known’ natural products, are increasing with the continued advance of microbial genome sequencing with next-generation sequencing approaches. To selectively identify these unknown known molecules, without first re-investigating (re-isolating) the known natural products will demand cutting-edge strategies to target them within the complex metabolomes in which they are found. Technologies will need to be sensitive enough to identify them when they are present in trace amounts and drive the production of these unknown agents with they are revealed in vanishing quantities. The proposed program will create powerful new platform technologies to selectively identify polyketide and nonribosomal peptide natural products by integrating numerous forms of ‘omic’ information with chemoinformatic and bioinformatic data processing strategies in conjunction with modern analytical instruments. The program will build significantly from the current NSERC-supported program that has produced several innovative works in developing an informatic search for natural products (iSNAP). Importantly this renewal will focus on the deployment of these technologies to selectively isolate new bioactive polyketide and nonribosomal peptides that considers the chemical ecology and systems in which they are found. I wish to advance the hypothesis, that the previous early golden age of antibiotic discovery driven by bioactivity guided activities revealed only a small fraction of the antibiotics that have been naturally evolved. My laboratory will interrogate the early organisms (producers of known antibiotics) that lead to the seminal discoveries in early antibiotic discovery, but instead of randomly assessing these organisms we will first obtain genomic sequences of them using instrumentation supported by my laboratories new CFI LOF infrastructure (genomic sequencers and mass spectrometers) and then leverage that genomic sequence to predict and selectively mine for known unknown natural products. Once these molecules are isolated we will then query their biological activities and specifically whether these unknown known molecules exhibit potent antimicrobial activities to drug resistant pathogenic bacteria and their collective activities (synergies).