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Due to the growing number of multi-drug resistant bacterial infections and the decline in number of FDA antibiotics over the past 3 decades, there is a dire need for the continued development and evaluation of structurally unique antibiotics with novel mechanisms of action. The Wolfe laboratory at UNC Asheville has contributed to this need through the development of a quantitative and high-throughput but “low-tech” method for screening bacterial libraries for antibiotic production in mono- and multi-culture. Using multi-culture to mimic a natural competitive environment allows for the isolation of potentially new bioactive secondary metabolites that are only produced under those conditions, which have yet to be discovered. Additionally, we use traditional medicinal chemistry to synthesize analogs of novel natural products (both ones we have isolated and ones isolated by other groups) in order to improve their antibiotic activity. This is exemplified in our work on pseudopyronine B and related analogs where we not only improved the activity of the natural product against Gram-positive bacterial, we also synthesized analogs that were active against Gram-negative bacteria unlike the natural product itself. We evaluate all of our isolated and synthesized antibiotics in house in broth microdilution bacterial cell death assays, anti-biofilm assays, and mechanism of action assay, which allow us to probe how the antibiotic is eliciting its bactericidal or bacteriostatic effects.
Recently, we have begun to focus specifically on inhibiting Pseudomonas aeruginosa (PA), a Gram-negative bacterium with multi-drug resistance that has been labeled as a “Serious Threat” by the CDC with 32,600 infections and 2,700 deaths per year in the US. To do this, we are developing potent and selective inhibitors of PA ATP synthase, which is a protein essential for all life, in collaboration with Dr. Ryan Steed (Chemistry, UNC Asheville) who is an expert in ATP synthase structure and function, and developing novel adjuvant therapies to reactivate known antibiotics so that they can be used to treat these infections.
