SarA as a Target for the Treatment and Prevention of Staphylococcal Biofilm-Associated Infection.

摘要

Genetic studies in the PI s laboratory demonstrated that mutation of the staphylococcal accessory regulator (sarA) limits biofilm formation inStaphylococcus aureus to a degree that can be correlated with increased antibiotic susceptibility and an improved therapeutic outcome in biofilm-associated infections. The goal of this project was to take therapeutic advantage of this observation by identifying small molecule inhibitors of sarA expression and/or function. To this end, we proposed two sets of experiments, the first being to carry out a large scale screen to identify inhibitors that offer the most promise. This was done using genetic reporter constructs proven to accurately reflect the functional status of sarA. The second was to then evaluate the therapeutic efficacy of the most promising inhibitors using established animal models of biofilm-associated infection. In our screen of >30,000 compounds, we identified 31 of potential interest, but secondary screens, including those assessing biofilm formation and the production of SarA itself, led us to focus on a single compound (ST028355). However, this compound was ultimately found to be unstable, thus greatly delaying and ultimately preventing our ability to carry out the intended in vivo studies. To overcome this, we began a collaboration with Dr. Peter Crooks, a medicinal chemist and Chairman of the Department of Pharmaceutical Sciences at the University of Arkansas for Medical Sciences. This led to the synthesis of over 200 analogs of this compound.