sarA as a Target for the Treatment and Prevention of Staphylococcal Biofilm-Associated Infection
Abstract
Genetic studies in the PI s 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 and/or 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. In the previous progress report, we identified 31 compounds of potential interest. Secondary screens of these compounds, including those focusing directly on biofilm formation, led us to focus on a single compound (ST014221). While we are continuing to the primary screen, we have continued to screen other sources including 24 additional compounds from TimTec that are structurally related to ST014221. This led to identification of a single compound that exhibits even greater activity than ST014221 in our reporter assay. However, we have been unable to carry out the secondary biofilm screen owing to solubility problems with this compound in our test medium. We are currently reaching out to medicinal chemistry collaborators to address this issue, thereby allowing us to prioritize these compounds with respect to each other. As additional compounds are screened, these will then be examined by direct comparison to the most promising of these compounds.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA590817
Entities
People
- Mark S Smeltzer
Organizations
- University of Arkansas for Medical Sciences