Structural Characterization of Aminoacyl-tRNA Synthetase Inhibitors as Antibiotics and Tools for Enzyme Mechanistic Studies
The alarming development and spread of resistance to our current stock of antibiotics is recognized as one of the major threats to human health in the 21st century. To combat this emerging crisis, efforts to develop drugs active against novel protein targets are of great importance. Aminoacyl-tRNA synthetases (aaRSs) catalyzing the formation of aminoacyl-tRNA, are clinically validated antibacterial targets. Using the non-hydrolysable aminoacyl-sulfamoyl adenosine (aaSA) as scaffold, various based substituted analogs targeting both classes aaRSs were synthesized aiming to understand how modifications or substitutions of the natural adenine base as part of the natural aaRS reaction intermediate, affect their inhibitory activity. The research project involves X-ray crystallographic studies with additional biochemical and biophysical characterization studies to develop a detailed 3D structure-activity relationship model of these synthesized inhibitors. Furthermore, the binding of inhibitors or substrates with the corresponding aaRSs usually results in conformational changes of the enzymes which will in turn help to understand their catalytic mechanism and determine the essential elements defining their activity and specificity. Combined these efforts will provide a framework for future antibiotic development.