One of the central adaptation mechanisms in bacteria is the ‘stringent response’, SR, which monitors the cellular translational status and orchestrates a multilayered control network. The SR is a core regulator playing the key role in virulence, formation of antibiotic-tolerant non-dividing persister bacteria and general antibiotic tolerance. Regrettably, technical challenges that have hampered our understanding of SR’s core molecular mechanism. However, with methodological developments revitalizing investigations of translation, the SR field is ready for decisive re-examination.
Our aim is to explore the molecular mechanisms of the SR with a powerful combination of in vitro and in vivo techniques, and to develop efficient approaches towards controlling it, providing an exciting novel strategy for disarming and pacifying pathogens. We employ a powerful combination of biochemistry, bioinformatics, organic synthesis and deep sequencing-based techniques, assisted with structural methods – cryo-electron microscopy and x-ray crystallography. There are three complementary research directions. First is investigation of the SR mediated by protein RelA using a reconstituted in vitro system. By obtaining information about molecular details of the SR, this provides a foundation for the other two directions: development of approaches for inhibition of the SR in live cells and global, ‘bird-eye-view’ characterization of the SR using the ribosome profiling deep-sequencing-based technique.