학술논문
Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Document Type
Original Paper
Author
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.
Source
Nature Communications. 13(1)
Subject
Language
English
ISSN
2041-1723
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.
Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.
Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.