Bill Wuest

 

The importance of natural products as anticancer and antibiotic compounds is undisputed due to their wide application as potent and effective pharmaceuticals. In contrast to broad-spectrum agents, the development of species-specific, “narrow-spectrum” antibacterials would be of interest to the medical community serving as novel therapeutics and also to microbiologists as chemical probes to deconvolute complex bacterial communities. Over the past five years our group has looked to Nature for inspiring chemical scaffolds and have leveraged diverted total synthesis (DTS) to develop inhibitors and probe molecules to study bacteria. 

 

Our efforts have focused on the rhizosphere, the area immediately surrounding the root system of plants, where Gram-negative organisms produce defense compounds to aid in their survival. Our group has investigated two such molecules, promysalin and carolacton, which specifically target P. aeruginosa (indwelling devices, multi-drug resistant) and S. mutans (dental caries, endocarditis), respectively. We have recently synthesized both natural products, confirmed their structure and biological activity, and identified novel phenotypes. More recently, we have utilized DTS to develop rational libraries through which the structure-activity relationships have shed light on the mechanism of action. In addition, this endeavor has provided analogs with unprecedented anti-virulence activity. The talk will highlight the conceptualization of the research hypotheses of both projects, the synthesis and evaluation of each class of analogs, and the current progress toward utilizing each set of molecules as chemical probes to better understand the chemical biology of bacterial biofilms.