Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2022-10, Vol.13 (1), p.5992-5992, Article 5992

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.