PROJECT SUMMARY
Salmonella infections are a leading cause of gastroenteritis in the US. The annual estimated burden is around
1 million cases domestically, and around 94 million cases worldwide. Prevention of Salmonella infection
focuses primarily on agricultural and food preparation practices. Interestingly, salicylate analgesics such as
bismuth subsalicylate (Pepto-Bismol) can be used to prevent gastroenteritis caused by Salmonella and closely
related enteric pathogens. The mechanism underlying the protective effects of these drugs is not fully
understood, but appear to be the result of changes in Salmonella physiology and metabolism induced by
salicylates. The premise of this research is to establish a molecular mechanism between salicylate treatment
and reductions in Salmonella virulence. Our emphasis is on the role of the homologous transcription factors
MarA, SoxS, Rob, and RamA. All four are activated directly or indirectly by salicylate drugs. Our preliminary
data show these transcription factors repress expression of key virulence genes in Salmonella. Proposed are
experiments to 1) define the regulatory interactions of MarA, SoxS, Rob, and RamA with Salmonella virulence
genes and 2) directly test the integrated effects of MarA, SoxS, Rob, and RamA on Salmonella adhesion and
invasion of epithelial cells. These data will establish MarA, SoxS, Rob, and RamA as important inhibitors of
Salmonella virulence, a class of critically understudied virulence regulators. Due to the broad conservation of
MarA, SoxS, Rob, and RamA in closely related bacteria, these transcription factors may be important inhibitors
of virulence traits in many other dangerous pathogens. With these findings in mind, developing compounds to
specifically activate MarA, SoxS, Rob, and RamA more selectively may provide more effective drugs to prevent
bacterial diarrhea.