Presenter: Billy Nguyen, College of Science, Chemistry
Authors: Dale A. Cummings Jr., Billy Nguyen, and Aaron W. Puri
Faculty Advisor: Aaron Puri, College of Science, Chemistry
Institution: University of Utah
Natural product research has played a dominant role in treating human disease and the majority of small molecule therapeutics in use today are derived from these compounds.Determining a natural product’s mode of action can be difficult and time consuming. The molecular target of a compound discovered through phenotypic assays is often particularly hard to elucidate. However, determining the mode of action of a natural product is necessary to optimize a compound’s properties and discover new therapeutic targets. The microsclerodermins are a family of polyketide-nonribosomal peptide hybrid natural products that exhibit potent antifungal activity and are known to induce apoptosis in a pancreatic cancer cell line. We recently discovered that the methane-oxidizing bacterium Methylobacter tundripaludum makes a natural product that inhibits the growth of the model yeast Saccharomyces cerevisiae. Genetic studies and analytical chemistry strongly suggest this compound is a microsclerodermin. We therefore plan to take advantage of having a microsclerodermin producer to determine the mode of action of these compounds. A first step is determining if the compound has a specific molecular target or acts nonspecifically, such as a detergent. Our results show that there is a delayed onset of cell death when yeast are treated with the compound. Furthermore, yeast in log phase are much more susceptible to the compound than stationary phase cells. Finally, we have isolated compound-resistant mutant strains of S. cerevisiae. Together, these results support the hypothesis that the microsclerodermins have a specific molecular target worthy of further investigation.