Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33736-5
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Funding
- Bill and Melinda Gates Foundation [OPP1066891, OPP1191579]
- Wellcome Trust [100195/Z/12/Z]
- BMGF [INV-010616, INV-004761, INV-004709, OPP 1177930, OPP1129600]
- TB Alliance
- Australia Aid
- Germany Federal Ministry of Education and Research through KfW
- Global Health Innovative Technology Fund
- Irish Aid
- Netherlands Ministry of Foreign Affairs
- UK Aid
- Intramural Research Program of the NIH, NIAID
- NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- Wellcome Trust [100195/Z/12/Z] Funding Source: Wellcome Trust
- Bill and Melinda Gates Foundation [INV-004761, OPP1191579, OPP1066891, INV-004709] Funding Source: Bill and Melinda Gates Foundation
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Tuberculosis is a major cause of mortality globally, and the emergence of drug-resistant strains of Mycobacterium tuberculosis necessitates the urgent development of safe and effective treatments. In this study, a compound against lysyl-tRNA synthetase is developed, demonstrating targeted mechanism of action and in vivo efficacy.
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.
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