Title: Isolation and characterization of small molecules mediating microbial symbioses
Description: Nature is unrivalled in its ability to create chemically-complex small molecules with diverse biological activities. These compounds have been evolutionarily selected by nature for their specific biological interactions, and represent a seemingly endless source of chemodiversity and biological potency. As a result, secondary metabolites from natural sources have long been recognized for their therapeutic potential and have provided the basis for some of our most useful drugs. There is a continual need for the discovery of new small molecules to provide new drug options and to battle resistance to existing drugs. As described in Chapter 1, the choice of biological system studied has a profound impact on the number and diversity of compounds isolated. The work reported herein describes the discovery of new bioactive small molecules from biological systems involving microbial symbioses. Due to the role small molecules play in mediating interactions between the microbes and their eukaryotic hosts, such systems have proven to be rich sources of secondary metabolites. Chapters 2 and 3 describe new strategies developed to understand the regulation of secondary metabolite production in bacteria engaged in complex trilateral symbioses with nematodes and insects. By identifying key triggers and regulatory genes controlling metabolite production, new biologically-active small molecules were discovered.

In Chapter 4, we discuss a symbiotic association between honey bees and a Streptomycete that protects the bees from a devastating bacterial pathogen. Chemical investigation of the protective strain led to the isolation of apinimycin, a new polyene macrolactam antibiotic. Chapter 5 describes the pursuit of a bacterial signaling molecule that induces multicellularity in choanoflagellates, unicellular eukaryotes considered to be the closest living evolutionary relatives to animals. Understanding the active molecule and its mechanism of action could provide insights into the origin of bacterial-eukaryotic interactions and the evolution of multicellularity in animals. Chapter 6 details the investigation of a number of symbiotic fungal species that live in the intracellular spaces of plants. Using a high-throughput antimalarial screen as a readout of biological activity, a structurally-diverse set of bioactive small molecules was isolated. Finally, Chapter 7 describes the isolation and characterization of three new pentacyclic terpenoid compounds from Bacillus subtilis .