The bacterial pathogen Staphylococcus aureus kills more people each year than HIV/AIDS. S. aureus can cause a range of infections including bacteremia and sepsis, severe pneumonia, infective endocarditis as well as a number of biofilm and implant associated infections, all of which can result in high morbidity and mortality. Due to increases in antibiotic resistance and spread of S. aureus in the community it is important to identify new and novel therapeutic targets. Mutation of the staphylococcal accessory regulator (sarA) leads to an attenuation of S. aureus. This attenuation has been demonstrated to lead to a decrease in intrinsic resistance in chronic biofilm associated infection models such as osteomyelitis. Our lab has previously identified an increase in secreted proteases as the reason for a sarA mutants decreased virulence. We hypothesize that the increase in protease expression would likely result in a decrease in virulence factors important for osteomyelitis. In this dissertation, we found that mutation of sarA significantly attenuated virulence in a model of post-traumatic osteomyelitis owing to protease mediated degradation of important virulence factors. As a result we wanted to establish if any one protease or subset of proteases is more important than others. We found that the metalloprotease aureolysin plays a greater role than any other individual protease. However concurrent mutation of multiple proteases shows the greatest attenuation in vivo. Proteomic analysis confirmed that this is the result of increased degradation of S. aureus proteins. Taken together, these finding have contributed to the understanding of how sarA regulates virulence factors and shows sarA is a viable target for the treatment of osteomyelitis.
|Advisor:||Smeltzer, Mark S.|
|Commitee:||Lee, Chia, Morrison, Richard, Ponnappan, Usha, Tackett, Alan|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Antibiotic resistance, Coagulase|
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