Pavel Kudrin will defend her doctoral thesis titled „In search for the inhibitors of Escherichia coli stringent response factor RelA“ on Monday, 30. October 2017 at 14.15.
Senior Research Fellow Vasili Hauryiliuk, professor Tanel Tenson
Gert Bange, PhD. Philipps-University Marburg (Germany)
Introduction of the problem.
Bacteria are the most abundant living organisms on Earth. Through billions of years of evolution they developed numerous adaptation mechanisms that allow them to survive in constantly changing environmental conditions. Bacteria protect themselves from various environmental challenges by entering a dormant state, by acquiring resistance to antibiotics, forming biofilms etc. All these varied adaptation mechanisms rely on the enzymatic activity of specific proteins that sense and response to stress – and that renders these proteins promising targets for the development of novel antibacterial agents.
The current work elucidates one of bacterial adaptive mechanisms called the stringent response that is orchestrated by RelA SpoT Homologue (RSH) enzymes in nutritionally poor environment, upon heat shock or cell wall damage. The varying level of effector-molecule of the stringent response – a highly charged nucleotide alarmone (p)ppGpp – is the key mediator of the survival program launched by bacteria during stringent response. In order to turn off the stringent response and increase the susceptibility of bacteria towards antibiotics, one can either target the RSH enzymes themselves or compromise the signaling nucleotide (p)ppGpp direclty.
Result and benefit
This dissertation discusses the possibilities of inhibiting the activity of Escherichia coli stringent factor RelA by re-examining the mechanism of action for the classical antibiotics and characterizing newly developed molecular tools based on a (p)ppGpp scaffold.
Nowadays the problem of antibiotic-resistant pathogenic bacteria is extremely important. The results achieved in the current work have a potential to be beneficial for clinical studies in order to switch off the stringent response and, therefore, reduce the resistance of bacteria towards antibiotics