Investigation of Natural Product Regulation within Streptomyces

More than 60% of all antifungal, antimicrobial, and anti-cancer drugs come from natural sources, such as plants, fungi, and bacteria; we call these nature-derived drugs Natural Products (NPs). One ‘super producer’ of NPs is the bacterial genus Streptomyces, with over 70% of therapeutic NP sourced from Streptomyces. These chemical weapons are regulated by sensitive signaling systems that respond to environmental conditions by activating ‘NP gene cluster’ expression, enzymes that biosynthesize NPs. Essential components of these signaling systems are Cluster Situated Regulators (CSRs); specific regulatory proteins of this class are transcription factors which can repress NP gene cluster expression until they sense a chemical signal. Previous research identified gamma-butyrolactones (GBLs), butenolides (BNs), and methylenomycin furans (MMFs) -small, low-concentration signaling molecules that affect morphological development- as ligands to a multitude of CSRs. These hormones are capable of inducing NP expression, thereby triggering production of therapeutically relevant NPs such as avermectin or streptomycin. This regulatory strategy is bioinformatically predicted to regulate potentially hundreds of novel NPs. My research objective is to elucidate signaling systems of Streptomyces which induce or enhance NP expression. To execute this, I first collaborated with organic chemists to derive a hybrid synthetic/biocatalytic approach to synthesizing these GBL-type hormones. I have developed a highly modular plasmid-based fluorescence reporter assay to identify CSR/ligand pairs. While these assays can aid in Natural Product discovery, they also have broad applicability for building novel genetic circuitry for use in synthetic biology.