Secondary Metabolites Program

The Secondary Metabolites Program targets the vast and underexplored reservoir of secondary metabolites produced by bacteria, fungi, algae and plants. These compounds are key to organisms' interactions with their environments and with each other, from defending against predators to aiding in symbiotic relationships and nutrient acquisition. However, secondary metabolite production is often not fully realized under standard laboratory conditions, with only a small portion of the biosynthetic gene clusters (BGCs) being expressed. The program works to uncover these hidden biochemical resources by exploring the genetic pathways responsible for their synthesis.

The Secondary Metabolites Program offers users extensive genomics, DNA synthesis and metabolomics capabilities to identify, express and characterize bioactive secondary metabolite compounds. To support users, our efforts include developing computational tools for predicting biosynthetic gene clusters (BGCs), advancing pathway analysis, optimization of cell- and cell free-based expression platforms, tools and data for deciphering regulatory networks, and refining experimental approaches to explore the synthesis and function of these biologically significant compounds.

By expanding the repertoire of secondary metabolites and improving the tools for their characterization, the program strives to facilitate the discovery of new bio-based molecules that can drive innovations in bioenergy, sustainable agriculture, and other fields reliant on natural product chemistry. These efforts will contribute to the broader goal of enhancing biotechnological applications, from biofuel production to improving the resilience and productivity of bioenergy crops.

• Development of cell-free based expression platforms: Only 10-20% of BGCs are expressed under standard laboratory conditions by their native hosts. We are developing cell-free based systems to express BGCs that alleviate the constraints of cells and allow for substrates to be directed towards secondary metabolite synthesis. We are currently exploring Escherichia coli and Streptomyces lysate systems.
• Deciphering regulatory networks of secondary metabolite biosynthesis: We have developed Regulon Identification by in vitro-sequencing (RIViT-seq) to identify RNA polymerase-sigma factor targets, and have expanded the sigma factor-target pairs twofold. We are also utilizing DNA-Affinity Purification (DAP) sequencing to express hundreds of transcription factors and determine their binding sites across multiple genomes.
• Computational prediction of heterologous expressability: We are developing a Heterologous Expression Report Card toolkit (HERC-tk) to enable users to identify the best host to express their BGC(s). This is based on extensive computational analyses of BGC size and complexity, BGC sequence composition, metabolic similarity & compatibility, and signatures of horizontal gene transfer.