Lysyl-tRNA synthetase a new target for M. tuberculosis drugs

Tuberculosis is a major global cause of both mortality and financial burden mainly in low - middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a novel drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series is the first to be developed against M. tuberculosis lysyl tRNA synthetase (LysS) and cellular studies support this mechanism of action. DDD02049209, the lead compound is efficacious in mouse models of acute and chronic tuberculosis infection and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains show no pre-existing clinical resistance towards this novel scaffold. DDD02049209 has now entered early toxicity studies, towards declaration as a preclinical development candidate. In addition, the first disclosure of the crystal structure of the M. tuberculosis LysS protein, supported the optimisation of the series to identify DDD02049209 and is enabling further structure-based drug discovery studies to identify alternative start points, as follow-on inhibitor series, for this novel target.