Marine natural products as antimicrobial chemical defenses and sources of potential drugs

Marine organisms are widely recognized sources of an impressive array of structurally unusual compounds. Marine natural products have exhibited interesting biomedical activities, provided targets for synthetic organic chemists, and afforded opportunities for elucidation of enzymatic mechanisms involved in biosyntheses of these molecules. Secondary metabolite pathways probably evolved to mediate interactions between organisms in their natural habitats; however, the ecological functions of natural products remain poorly understood for the vast majority of cases. In the present series of investigations, I evaluate the hypothesis that macroalgal natural products play a role in defending these organisms against potentially pathogenic microbes in the marine environment. Further, I combine these ecology-driven investigations with evaluation of algal natural products as sources of novel human drugs. This combined approach resulted in discovery of 15 novel natural products from two tropical red algae, Callophycus serratus and an unidentified crustose red alga. These new molecules included seven novel carbon-carbon connectivity patterns, not previously reported in the synthetic or natural product literature, illustrating the abundance of secondary metabolite diversity among marine macroalgae. Further, many compounds exhibited both biomedical and ecological activities, suggesting the synergistic potential of combined biomedical/ecological investigations in providing drug leads as well as insights into the natural functions of secondary metabolites. Bromophycolides and callophycoic acids, natural products from C. serratus, inhibited growth of the marine fungal pathogen Lindra thalassiae. Spatially-resolved desorption ionization mass spectrometry (DESI-MS) revealed that antifungal natural products were found at specific sites on algal surfaces. The heterogeneous presentation of antimicrobial chemical defenses on host surfaces suggests the potential importance of spatial scale in understanding host-pathogen interactions, and illustrates the capacity of mass spectrometry imaging in understanding chemically-mediated biological processes. Finally, assessment of antimicrobial chemical defenses among extracts from 72 collections of tropical red algae revealed that nearly all algae were defended against at least one marine pathogen or saprophyte and further suggested the untapped potential of ecological investigations in the discovery of novel chemistry.Ph.D