Molecular mechanisms of the bacterial stringent response
PI: Vasili Hauryliuk, PhD, associate professor,
Ragnar Söderberg Fellow in Medicine 2014
Department of Molecular Biology
Our research topic is the bacterial stringent response - an adaptation mechanism mediated by the alarmone nucleotide ppGpp, which exerts its regulatory role by attenuating the activity of numerous enzymes, with RNA polymerase being the main target. The intracellular levels of ppGpp are controlled by the RelA-SpoT Homologue (RSH) family of proteins, which either synthesize or hydrolyze ppGpp in response to various stress stimuli. Since the stringent response is implicated in regulation of bacterial virulence, antibiotic tolerance and biofilm formation, development of specific inhibitors of the stringent response is a promising strategy for the design of novel antimicrobials.
We utilize a combination of experimental and in silico approaches. Using an in vitro stringent response system, we demonstrated that the E. coli RelA protein is activated by its product ppGpp, thus creating a regulatory positive feedback loop. By means of sensitive bioinformatic sequence searching we identified 30 RSH families, and now we work on uncovering the architecture of the ppGpp-mediated cross-talk between various RSH members. Our in vivo single molecule experiments led to the formulation of the ‘extended hopping’ mechanism of RelA’s catalytic cycle. Capitalizing on these findings and developed methodologies, we are now working on identification of specific stringent response inhibitors.
Our research is currently supported by the Swedish Research Council, Kempe foundation, Ragnar Söderberg foundation, Swedish Foundation for International Cooperation in Research and Higher Education, and Umeå University funds.