Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Simon R. Green, Susan H. Davis, Sebastian Damerow, Curtis A. Engelhart, Michael Mathieson, Beatriz Baragaña, David A. Robinson, J. Tamjar, Alice Dawson, Fábio K. Tamaki, Kirsteen Buchanan, John Post, Karen Dowers, Sharon M. Shepherd, Chimed Jansen, Fabio Zuccotto, Ian H. Gilbert, Ola Epemolu, Jennifer Riley, Laste Stojanovski, Maria Osuna‐Cabello, Esther Pérez‐Herrán, María José Rebollo Espinosa, Laura Guijarro López, Patricia Casado, Isabel Camino, Heather Kim, James Bean, Navid Nahiyaan, Kyu Y. Rhee, Qinglan Wang, Vee Y. Tan, Helena I. Boshoff, Paul J. Converse, Si‐Yang Li, Yong S. Chang, Nader Fotouhi, Anna M. Upton, Eric L. Nuermberger, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Laura A. T. Cleghorn
Abstract
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.