|
With the steady emergence and spread of antibiotic resistant pathogens, the development of new antibiotics is increasingly important. This research program will study the mechanisms of antibiotic function in order to develop novel antibiotics. In particular antibiotics that target the cellular machinery of the pathogen, that is responsible for translating genetic information into functional proteins. A process called translation. The detailed understanding of the involved processes is of fundamental importance for the development of new types of antibiotics. In our research program we will study, on the molecular level, how antibiotics interfere with these processes, in order to inhibit translation. We will identify the molecular requirements for the inhibition of translation and analyze how resistance mechanisms work. On the basis of these results we will develop novel tests that will allow us to search for chemical compounds that will effectively inhibit translation. The research will significantly contribute to our understanding of the structural and functional requirements of antibiotic function, providing the framework for rational inhibitor design.
|
|
|
During translation, growth of the polypeptide chain is facilitated by consecutive binding of two Elongation factors (EF), Tu and G, to the elongating ribosome. Protein molecules are intrinsically flexible, and typically undergo a wide variety of motions at normal temperatures. Crystal structures of the free EFs as well as Cryoelectron microscopic studies of ribosome-bound EFs demonstrated a high degree of conformational flexibility to be important for the function of these factors. The flexibility and dynamics of proteins such as elongation factors has been optimized by evolution for their activities and functions. In order to analyze the role of the dynamical properties on their function, and to bridge the gap between the static structural data and the huge amount of biochemical and kinetic information that is available, the conformational flexibility of elongation factors such as EF-Tu and EF-G is studied using molecular dynamics simulation and structural alignments.
|
|
