Tyrosine-tRNA synthetase as target for the development of new antibacterial lead structures

The alarming spread of bacterial resistance to existing antibiotics is a serious global threat for human health. As a result, there is an urgent need for new antibiotics, preferably acting on new cellular targets that are essential for the survival of pathogens. As part of the protein synthesis machinery, aminoacyl-tRNA synthetases (aaRSs) have been identified as validated targets for the development of antimicrobial agents. The crucial challenge is the development of appropriate antibacterial lead compounds with good specificity for bacterial aaRSs with the aim of achieving an optimal therapeutic ratio. Hereto, both the lab for medicinal chemistry (LMC) and the lab for biocrystallography (LB) teamed up their expertise and set out on a joint structure based drug design (SBDD) campaign to tackle this issue. The ultimate goal of this specific project is the synthesis and development of new tyrosyl-tRNA synthetase inhibitors. Chemical synthesis will be combined with structural analysis of the ligandenzyme complexes (by our LB partner) to facilitate lead design and optimization.