Salmonella enterica serovar Typhimurium (S. Typhimurium) is a model enteric pathogen. Like many pathogens, S. Typhimurium requires iron for survival both in the environment and in the host. However, when host defenses damage iron containing bacterial proteins, intracellular free iron acts as a catalyst for production of free radicals. IceT is a stress-induced transporter in the major facilitator superfamily that is conserved throughout the Enterobacteriaceae. Its expression in S. Typhimurium leads to efflux of iron and citrate, which protects the bacteria from a variety of stresses and antibiotics. The goal of this proposal is to further characterize this intrinsic mechanism of bacterial stress resistance and understand its role in S. Typhimurium virulence. This will be accomplished by characterizing the specific substrates transported by IceT and elucidating the chemistry of transport, examining structure-function relationships in the IceT protein, and characterizing a homologue of IceT, YieO, that is also found in S. Typhimurium and may play a complementary role in intrinsic resistance to host defenses and antibiotics. Experiments will be conducted in vitro, in culture, and in a murine model of infection. These studies will provide insight into the function of two representative members of the major facilitator superfamily and the role regulation of bacterial metabolism plays in resistance to stress.
Salmonella is a human and animal pathogen that has intrinsic mechanisms for resisting the actions of the host immune system, as well as antibiotics. This project proposes to characterize stress-induced transporters that alter Salmonella metabolism, thus conferring resistance. This will expand our knowledge of how bacteria defend themselves and ultimately contribute to the development of new therapeutic strategies.
|Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Discrimination and Integration of Stress Signals by Pathogenic Bacteria. Cell Host Microbe 20:144-53|
|Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Bacterial Stress Responses during Host Infection. Cell Host Microbe 20:133-43|
|Frawley, Elaine R; Fang, Ferric C (2014) The ins and outs of bacterial iron metabolism. Mol Microbiol 93:609-16|