Natural products, or compounds isolated from biological sources, account for the vast majority of current pharmaceuticals. Many of these pharmaceuticals produced revolutionary medical advances at the time of their discovery, such as the antibiotics penicillin (isolated from Penicillium fungi) and tetracycline (isolated from Streptomyces). Our lab is focused on the chemical diversity and bioactivity of the natural products of microorganisms, with a specific focus on compounds with medical applications. Our research approach is motivated by the idea that 1) there are many chemically and biologically interesting compounds produced by under-explored microorganisms such as endophytic fungi and rare actinomyctes still awaiting discovery; 2) protein targeted bioactivity assays are the most efficient method to identify these compounds; and 3) understanding the molecular basis for this bioactivity is critical for subsequent efforts to improve activity and obtain viable drug leads.
Ongoing projects in our lab include screens of the natural products of endophytic fungi and rare actinomyctes for compounds with anti-cancer, antibacterial, and anti-viral activity. These screens utilize fast and efficient biosensor assays to identify compounds that bind to disease related target-proteins, and are supplemented by cell-based assays. The mechanism of action of the isolated compounds is subsequently determined by biophysical techniques, pull-down experiments, NMR methods, and semi-synthetic approaches.
Antivirals: Although therapies for treating hepatitis C (HCV) are improving, no vaccine is available and current standard therapy is still ineffective in 10% of US patients and is limited by the rapid development of resistance. Ongoing projects in our lab include work to develop novel screening platforms capable of identifying antivirals from microbial sources with high throughput and high sensitivity.
Anti-cancer: In one ongoing project of our lab, we are examining the mode of action of the potent anti-cancer active compound mensacarcin. Previous studies from our lab identified the active pharmacophore and showed that the anti-cancer activity is modulated by the electrophilie of the side chain. In the future, we will use immune-staining, cell-cycle tests, autophagy and apoptosis specific cell assays to determine its mode of action.
Antibacterial: Fractions and pure compounds from our strain library of endophytic fungi have shown potent inhibitory activity against a diverse panel of bacterial human pathogens. We are particularly interested in identifying compounds that inhibit multi-drug resistant strains of Staphylococcus aureus, which have emerged as a substantial public heath threat.
Carbohydrate mediated interactions play a critical role in a multitude of biological processes. Glycan recognition is critical to uncountable aspects of human physiology, including sperm-egg fertilization, cell homing, and the trafficking of proteins within a cell. Furthermore, the vast majority of microorganisms and pathogens are coated with glycans that mediate their interactions with their environment. Several ongoing projects in our lab are focused on understanding the molecular basis of glycan-protein recognition.