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, Jevgenia Tamjar, Alice Dawson, Fabio K. Tamaki, Kirsteen I. Buchanan, John Post, Karen Dowers, Sharon M. Shepherd, Chimed Jansen, Fabio Zuccotto, Ian H. Gilbert, Ola Epemolu, Jennifer Riley, Laste StojanovskiMaria Osuna-Cabello, Esther Pérez-Herrán, María José Rebollo, Laura Guijarro López, Patricia Casado Castro, Isabel Camino, Heather C. Kim, James M. Bean, Navid Nahiyaan, Kyu Y. Rhee, Qinglan Wang, Vee Y. Tan, Helena I.M. 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number5992
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


Dive into the research topics of 'Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs'. Together they form a unique fingerprint.

Cite this