PROJECT SUMMARY/ABSTRACT Natural products from bacteria continue to be the frontline defense in the struggle against bacterial infections, and have also found wide use as antifungals, anthelminthics, anti-cancer drugs, and immunosupressants. One group of bacteria, the actinomycetes, has historically been the deepest source of clinically-useful natural products. Over the last decade, numerous reports have demonstrated that natural product biosynthesis often occurs in the context of actinomycete interactions. These include interactions between microbes of different species, and cell-cell coordination within colonies of single actinomycetes. Together, these findings have solidified the idea that induction of natural product biosynthesis is socially driven in these bacteria. Despite the importance of this social aspect, how these interactions unfold at the molecular level and how interactions may best be harnessed for natural products discovery remain open questions. The goals of this study are to understand how inter- and intra- species interactions activate natural product biosynthesis at the molecular and systems levels, and to build framework for translating these insights into natural product discovery. First, this work will examine how the model actinomycete Streptomyces coelicolor activates expression of genes for antibiotic production in the presence of other actinomycetes. This activation requires an unusual and poorly understood signal transduction mechanism found in actinomycetes that shares parallels with eukaryotic systems that rely on G protein activation. Second, this work seeks a systems- level understanding of spatially coordinated antibiotic production within individual S. coelicolor colonies. Knowledge generated from this objective may be employed to someday manipulate cell fates within actinomycete cultures to drive natural products discovery and production. Third, this work leverages actinomycete interactions for the discovery of novel natural products. This research serves as a testbed for putting our knowledge of actinomycete interactions into practice, with an emphasis on discovery of compounds with unusual mechanisms of action. In its entirety, this work will illuminate the social drivers of natural product biosynthesis, and in the long term, provide a foundation for harnessing microbial social cues and genetic regulation to maximize future natural products discovery efforts.