Isolation of Natural Products from Marine Actinomycetes and their Selective Therapeutic Properties

Over the course of the last 10 years marine actinomycetes have become the frontier of natural products chemistry yielding a large number of biologically important compounds. The MacMillan lab has developed new techniques to isolated >400 unique species of marine actinomycetes from marine sediments collected in a variety of microbial habitats, such as mangroves, hypersaline lakes and estuaries. My research efforts have focused on using a library of natural product fractions created from these bacterial strains to screen for molecules that exhibit selective cytotoxicity against a panel of tumor derived cell lines that include lung, colon, melanoma, pancreatic cancer and glioblastoma. Screening of ~1200 fractions has resulted in a variety of active fractions that display unique activity profiles. A thorough analysis of the activity profiles has revealed >20 fractions that exhibit selective cytotoxicity, while a large number of fractions (>150) showed broad spectrum cytotoxicity. One of the most selective fractions exhibited an IC₅₀=13.2nM against the glioblastoma cell line T98G, while 10-100 times less potent against other lines.  To determine our metabolites mode of action we utilized a fairly novel approach which is genomics that utilizes selection experiments by generating random mutations on the cell, which will unveil the gene target and therefore the natural products protein target. This approach will be confirmed using biochemical techniques. In conclusion, we have used a combination of chemical, biochemical and genetic techniques to determine the chemistry and biology of this and other natural products.