Structural and functional studies on novel bacterial lysine-deacetylases and their roles in bacterial physiology and during bacterial infection.

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Lysine-acetylation is a post-translational modification that is tightly connected to the cellular metabolism. Dysfunction in the lysine-acetylation modifcation system results in the development of severe diseases ranging from cancer to neurodegenerative diseases and metabolic diseases. Lysine-acetyltransferases catalyze the transfer of the acetyl-moiety from acetyl-CoA to the lysine side chain, and deacetylases remove it. Deacetylases can be classified into NAD+-dependent Sirtuins and Zn2+-dependent classical deacetylases (KDACs). So far, most research on deacetylases in prokaryotes focussed on a single sirtuin deacetylase. We applied a bioinformatics approach and identified thousands of novel classical KDACs in prokaryotes. Several KDACs are encoded in pathogenic Gram-positive and Gram-negative bacteria, such as Legionella pneumophilae, Vibrio cholerae, Klebsiella pneumoniae and Staphylococcus aureus. For one KDAC from K. pneumoniae, a severe human pathogen, we could solve crystal structures in the apo-form and in the complexes with inhibitors. In this research proposal will combine synthetic biological approaches, structural biology with microbiological approaches and mass-spectrometry to understand how selected novel prokaryotic KDACs affects bacterial physiology and pathophysiology. Post-translational lysine-acetylation is a way to sense metabolic changes in the cellular environment and to translate these changes to regulate cellular processes by altering protein function. As bacteria, and particularly pathogenic bacteria, have to respond fast to alterations in their environment and to adopt to these conditions, lysine acetylation might play an important role in these processes. The results obtained in this project will not only help to understand the role of lysine acetylation in normal bacterial physiology, it will also be valuable to explore the potential of a novel therapeutic strategy tackling the lysine acetylation machinery to treat severe bacterial infections. This topic is currently highly important considering the spread of multi-resistant bacterial strains in the environment, which can lead severe problems when those strains spread in hospitals.