Disease causing bacteria encounter harsh environments in the human airways and must adapt to survive. In bacterial pathogenesis, before bacterium reach nutrient rich environments like the blood and gut, they must scavenge alternative nutrients like sialic acid- an energy and nitrogen rich carbohydrate1. Bacteria, like Streptococcus pneumoniae, use transcriptional regulation to sense the available sugars and upregulate the appropriate machinery. The nan regulatory protein, NanR, from Streptococcus pneumoniae binds a sialic acid metabolite and upregulates DNA transcription in response2. By studying this protein-DNA system in vivo and in vitro we are working to uncover the mechanism of sugar-sensing and transcriptional regulation that occurs during mammalian infection in Streptococcus pneumonia. We present several high-resolution crystal structures including the first full length NanR protein bound to its DNA recognition sequence. These structures have uncovered a unique mechanism of ligand binding and transcriptional regulation, and thus we propose a rare DNA looping hypothesis that upregulates transcription in the presence of the sialic acid metabolite. By making a knockout model in Streptococcus pneumoniae and measuring transcription flux, we are excited to show validation of this hypothesis and the mechanism of sialic acid regulation.
1 Buckwalter, C. M. & King, S. J. Pneumococcal carbohydrate transport: food for thought. Trends Microbiol 20, 517-522 (2012). https://doi.org:10.1016/j.tim.2012.08.008
2 Afzal, M., Shafeeq, S., Ahmed, H. & Kuipers, O. P. Sialic acid-mediated gene expression in Streptococcus pneumoniae and role of NanR as a transcriptional activator of the nan gene cluster. Appl Environ Microbiol 81, 3121-3131 (2015). https://doi.org:10.1128/AEM.00499-15