dissertationDrug discovery and development from marine invertebrates has been fraught with two key problems, namely, the variability of occurrence and limited supply. Bacteria in symbiosis with marine invertebrates have been shown to produce most bioactive natural products isolated from these organisms, and thus are central to addressing questions of occurrence and issues of supply. Specifically, the factors that influence symbiosis influence the distribution and supply of natural products. This dissertation sought to address these two problems through studies in symbiosis and supply of symbiotic natural products. First, the global patterns of chemical symbiosis in marine ascidians, a group of highly prolific producers of natural products, were examined. Symbiosis in ascidians is shown to be host-specific (meaning that similar species of invertebrates contain similar bacterial symbionts); further, microbiomes are shown to be equally diverse regardless of location. Secondary metabolism was also found to be host-specific, but is more sensitive to biogeographical factors as evidenced by the increase in the potency of the secondary metabolites in tropical regions. To address the supply of rare natural products, heterologous expression was used to produce useful quantities of a group of symbiotic natural products, cyanobactins. Using metabolic engineering, a platform was developed to supply cyanobactins in high-titer, and its usefulness showcased in the discovery of ! novel activities of these natural products. Another facet of the supply problem is the substantial difficulty involved in synthesizing derivatives of natural products, which generally requires total chemical synthesis. On this aspect of the supply problem, the capacity of the cyanobactin pathway to generate unprecendented structural diversity by the incorporation of non-proteinogenic amino acids into this multistep, substrate-tolerant biosynthetic pathway was demonstrated
