Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Nature communications, Volume: 13, Issue: 1
October 11, 2022
Simon R Green SR, Susan H Davis SH, Sebastian Damerow S, Curtis A Engelhart CA, Michael Mathieson M, Beatriz Baragaña B, David A Robinson DA, Jevgenia Tamjar J, Alice Dawson A, Fabio K Tamaki FK, Kirsteen I Buchanan KI, John Post J, Karen Dowers K, Sharon M Shepherd SM, Chimed Jansen C, Fabio Zuccotto F, Ian H Gilbert IH, Ola Epemolu O, Jennifer Riley J, Laste Stojanovski L, Maria Osuna-Cabello M, Esther Pérez-Herrán E, María José Rebollo MJ, Laura Guijarro López L, Patricia Casado Castro P, Isabel Camino I, Heather C Kim HC, James M Bean JM, Navid Nahiyaan N, Kyu Y Rhee KY, Qinglan Wang Q, Vee Y Tan VY, Helena I M Boshoff HIM, Paul J Converse PJ, Si-Yang Li SY, Yong S Chang YS, Nader Fotouhi N, Anna M Upton AM, Eric L Nuermberger EL, Dirk Schnappinger D, Kevin D Read KD, Lourdes Encinas L, Robert H Bates RH, Paul G Wyatt PG, Laura A T Cleghorn LAT

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and 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 drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.