sarA as a Target for the Treatment and Prevention of Staphylococcal Biofilm-Associated Infection
Annual rept. 30 Sep 2011-29 Sep 2012
ARKANSAS UNIV AT LITTLE ROCK MEDICAL CENTER
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Genetic studies in the PIs laboratory have demonstrated that mutation of the staphylococcal accessory regulator sarA limits biofilm formation in Staphylococcus 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 is to take therapeutic advantage of this observation by identifying small molecule inhibitors of sarA expression andor function that could be used together with conventional antibiotics to achieve the desired therapeutic outcome. This will require two sets of experiments, the first being to carry out a large scale screen of potential inhibitors to identify those that offer the most promise. This is being done using genetic reporter constructs proven to accurately reflect the functional status of sarA. The second is to then evaluate the therapeutic efficacy of the most promising inhibitors using established animal models of biofilm-associated infection. While we are continuing to expand the primary screen, we have identified 31 small molecules that we believe warrant further consideration, and we are currently carrying out expanded secondary screens, including assays of biofilm formation itself, to both verify the activity of these compounds and rank them by comparison to each other. As additional compounds are screened, these will then be examined by direct comparison to the most promising of these compounds. This will put us in a position to undertake the second objective of evaluating the impact of the most promising of these inhibitors with respect to both inhibiting S. aureus biofilm formation and relative antibiotic susceptibility in the specific context of an established biofilm.
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