טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentNawatha Mickal
SubjectBacterial Tyrosine Kinases as Targets for Novel
Antibacterial Drugs:Towards Structure-based Drug
Design
DepartmentDepartment of Biology
Supervisor Professor Meytal Landau
Full Thesis textFull thesis text - English Version


Abstract

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The frightening rapid increase in the occurrence of antibiotic resistance to many common bacterial pathogens calls for an immediate demand for new classes of antibacterial agents. Bacterial tyrosine kinases (BY-kinases) have recently emerged as potential attractive drug targets, being vital for core bacterial processes, while having no homology to mammalian proteins. Accordingly, developing inhibitors to BY-kinases might offer new, safe and effective antibacterial drugs.

     We selected eight BY-kinases from different bacterial species, including seven pathogens and one probiotic bacteria. Our goal was to better understand the features that distinguish between BY-kinases of different organisms. The selected eight BY-kinase genes were successfully cloned and expressed in Escherichia coli.

     We determined the crystal structure of the BY-kinase from Burkholderia cepacia, named BceF, at 2.2Å resolution. B. cepacia is an important human pathogen, which causes pneumonia in immunocompromised individuals. BceF is involved in the production of exopolysaccharides, which are a part of the biofilm matrix formed by B. cepacia and thus important to its virulance. Our working hypothesis is that structure-based design of inhibitors to BceF will provide leading anti-bacterial compounds against a key virulence determinant.

     We initiated the development of kinase activity assays in order to test the activity of BceF, and to later test potential inhibitors. We collaborated with Prof. Nir Ben-Tal (Tel-Aviv University) in order to screen, in-silico, libraries of small-molecule compounds, which will bind to the BceF active site and inhibit its activity. The testing of the small molecule is now an ongoing project at the lab. 

     This project is significant on two levels: within protein science, BY-kinases raise fundamental questions regarding activation and regulation mechanisms in bacteria-specific tyrosine kinases. Within translational biology and medical sciences, BY-kinases present targets for the development of novel and safe antibacterial drugs.