Salmonella infections are responsible for an estimated 3 million annual deaths worldwide. Multidrug resistance among clinical Salmonella more than doubled from 2011 to 2013. The World Health Organization has ranked Salmonella as one of the top 12 antibiotic resistant bacterial threats to global health. The goal of this Research Career Scientist Award is to continue with our efforts to apply our knowledge of Salmonella virulence to the development of novel antibiotics against multidrug resistant bacterial pathogens. Resistance of Salmonella and other pathogenic bacteria to antibiotics is in great part regulated by the nucleotide alarmone guanosine tetraphosphate and the DksA protein. Both of these mediators bind to the secondary channel of RNA polymerase, regulating transcription of central metabolic pathways and a variety of virulence programs. We will carry on our research on the molecular mechanisms by which guanosine tetraphosphate and DksA regulate Salmonella transcriptional programs. The Research Career Scientist Award will also allow us to develop novel antibiotics that inhibit DksA-dependent bacterial transcription. Binding of DksA to the secondary channel of RNA polymerase is in competition with Gre transcription elongation factors. We have found that Gre proteins are needed for Salmonella virulence and the resistance of this Gram-negative rod to antibiotics. We plan to characterize the molecular mechanisms by which Gre factors promote bacterial pathogenesis and antibiotic resistance. These research projects are highly collaborative in nature, involving scientific interactions with investigators at the Veterans Affairs Eastern Colorado Healthcare System, the Atlanta VA Medical Center and the Veterans Administration Ann Arbor Healthcare System. I plan to continue fostering these productive collaborations. Training of junior faculty, graduate students and postdoctoral fellows are also important components of this Research Career Scientist Award. Moreover, in collaboration with other investigators at the at the Veterans Affairs Eastern Colorado Healthcare System and Wisconsin-Madison VA Medical Center, we will continue mentoring promising CDA- 2 candidates, and thus help train the next generation of outstanding VA scientists.
Nontyphoidal Salmonella are a common cause of diarrhea in healthy individuals and a fatal systemic complication in patients with underlying immunodeficiencies. Salmonella is the most common cause of bacteremia in HIV--?infected people. Salmonellosis is a frequent infection in veterans, their families and military personnel deployed abroad. Salmonella and other bacteria associated with diarrhea are increasingly becoming resistant to multiple antibiotics. The Center for Disease Control?s National Resistance Monitoring System reported that roughly 20% of Salmonella blood isolates in the US are resistant to first--?line drugs. We will continue to build on our understanding of Salmonella pathogenesis for the development of novel therapeutics against multidrug resistant Salmonella and other bacteria.