Rational design of tRNA synthetase inhibitors as new antibacterials.

There is a compulsory societal need for the development of new and efficient antibiotics. Mechanistically the inhibition of protein synthesis is a longstanding and validated strategy. This can be accomplished by selectively inhibiting bacterial aminoacyl-tRNA synthetases (aaRSs). Guided by structure-based drug design, the present project proposes the development of several new classes of inhibitors derived from either natural origin or known sulfamate nucleoside scaffolds. High resolution structures of both human and bacterial aaRSs in complex with known inhibitors will guide the development of new ligands with improved selectivity. In parallel new chemical strategies will be employed to enhance delivery of the active component into the bacterial cell. The proposed collaborative efforts aim to yield potent new compounds to add to the dwindling antibacterial armory.

Keywords:sulfonamides, nucleoside analogs, prodrugs, X-ray crystallography, tRNA synthetases, in vitro affinity, antibiotics, structure-based drug design

Disciplines:Other biological sciences