The Center will apply state-of-the-art genomics and metabolomics approaches to guide the discovery of high value leads produced by under-explored sources of biological diversity. We will focus on compounds that have evolved to be functional through mediation of symbiotic communication between microbes and hosts. The In vitro Core (Core B) scientists will work collaboratively with Professor Bugni's laboratory to produce and purify natural products provided by all three projects in the Center. Core B scientists will assess the anti-microbial activities of extracts, fractions and compounds against drug resistant target pathogens by leveraging the high throughput assay infrastructure and expertise currently available in the UW Small Molecule Screening and Synthesis Facility (SMSSF) and Professor Bugni's laboratory. Doseresponse properties in the antimicrobial assays will be evaluated to prioritize the selection ofthe most potent compounds with broad, cidal activity that causes the death of microbial cells in culture. Compounds with antimicrobial activity then will be assessed for cytotoxicity on primary human cells in order to eliminate toxic compounds early in the projects. Core B scientists also will be responsible for scale-up production of pure compounds (selected by the Center PI and Project leaders) using optimized fermentation approaches developed in Professor Bugni's laboratory and production-scale purification infrastructure. Compounds will be evaluated for stability, solubility and formulation through coordination with the UW School of Pharmacy Pharmaceutical Experiment Station. Sufficient quantities ofthe pure compounds will be provided to Core C for testing the efficacy and safety of the compounds in mice and to Core D, the Mechanism of Action Core. Core B will provide medicinal chemistry expertise to evaluate potential synthetic strategies for simplified analogs and/or for semisynthetic derivatization to improve the pharmacokinetics of scaffolds or determine structure-activity-relationships.
There are no effective therapies for the emerging resistant pathogens that are becoming an increasing threat to the public health. The goals of the Center are to provide new, broad spectrum antimicrobial agents through a collaborative focus on high value natural product leads produced by under-explored sources of biological diversity.