As microbial genome sequencing becomes more widespread, the capacity of microorganisms to produce natural products is coming into better view. This competing renewal surveys this capacity using the latest in computational and expression screening approaches to target specific sub-classes of natural products that emerge from a fundamentally new platform for discovery of natural products from the microbial world. Described here is the pursuit of specific set of natural products and their gene clusters which have emerged from a new approach that achieves large-scale pairing of biosynthetic gene clusters with their small molecules to facilitate discovery. From a library of 178 actinobacteria strains, a genome-enabled metabolomics approach was used (a.k.a., “metabologenomics”) to correctly identify natural products and correlate them with their biosynthetic gene clusters. The proposed research extends this method to examine unknown metabolites, the mobymycins (Aim 1) and rimosamides (Aim 2), each with their respective clusters exhibiting unusual biosynthetic mechanisms and monomers, such as the new amino acid, “tambroline” (see Aim 1). In the first two aims, the precise structures, biosynthetic details and in the case of mobymycin—the protein binding target(s) of these new natural products will be defined. In Aim 3a, the defined set of new gene cluster–compound pairs will be mined in silico for those that terminate in reductase domains, and therefore likely harbor electrophilic warheads from reductive off-loading of thiotemplate assembly lines. Aim 3b proposes screening a set of 31 bona fide new compounds (each with a strain known to produce the compound) for those with bioactivity in phenotypic screens using C. elegans, along with standard anti-proliferative and anti-fungal assays. Mining the microbial world with “metabologenomics” is innovative and a represents a major shift from past activities in this R01 grant (which led to sixteen publications over the past granting period). With a set of new compounds and their biosynthetic gene clusters in hand, the investigators will pursue several of these in targeted mode. Beyond the direct impact of this proposal, the work provides a major path forward which adds momentum to an ‘omics’-driven resurgence in natural products discovery. Such a resurgence promises a more deterministic path for structure-based discovery of natural products and to provide these structures at a rate not seen before in the field (a.k.a. “high throughput discovery” as described in recent literature). In essence, the proposed research will demonstrate the value of regularizing a strain collection into a library of compounds, which are known to be expressed and possess particular sub-structures (e.g., an electrophilic warhead). These value propositions serve as motivating rationales to merge a new kind of discovery pipeline containing unique molecular structures with assays for bioactivity.
|Effective start/end date||4/1/16 → 8/4/22|
- National Center for Complementary and Integrative Health (5R01AT009143-17)
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