Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs Journal Article
| Authors: | Green, S. R.; Davis, S. H.; Damerow, S.; Engelhart, C. A.; Mathieson, M.; Baragaña, B.; Robinson, D. A.; Tamjar, J.; Dawson, A.; Tamaki, F. K.; Buchanan, K. I.; Post, J.; Dowers, K.; Shepherd, S. M.; Jansen, C.; Zuccotto, F.; Gilbert, I. H.; Epemolu, O.; Riley, J.; Stojanovski, L.; Osuna-Cabello, M.; Pérez-Herrán, E.; Rebollo, M. J.; Guijarro López, L.; Casado Castro, P.; Camino, I.; Kim, H. C.; Bean, J. M.; Nahiyaan, N.; Rhee, K. Y.; Wang, Q.; Tan, V. Y.; Boshoff, H. I. M.; Converse, P. J.; Li, S. Y.; Chang, Y. S.; Fotouhi, N.; Upton, A. M.; Nuermberger, E. L.; Schnappinger, D.; Read, K. D.; Encinas, L.; Bates, R. H.; Wyatt, P. G.; Cleghorn, L. A. T. |
| Article Title: | Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs |
| 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. © 2022, The Author(s). |
| Keywords: | controlled study; protein expression; unclassified drug; mortality; nonhuman; mouse; cytology; protein targeting; animal experiment; animal model; in vitro study; mycobacterium tuberculosis; crystal structure; linezolid; macrophage; crystallization; biochemistry; enzyme assay; antimycobacterial agent; tuberculosis; pyrimidine; growth inhibition; dna isolation; crystallography; kanamycin; mortality rate; oxazolidinone derivative; male; article; whole genome sequencing; evaluation study; middle income country; anhydrotetracycline; bedaquiline; lysine transfer rna ligase; lysine transfer rna ligase inhibitor; pretomanid; experimental tuberculosis |
| Journal Title: | Nature Communications |
| Volume: | 13 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-10-11 |
| Start Page: | 5992 |
| Language: | English |
| DOI: | 10.1038/s41467-022-33736-5 |
| PROVIDER: | scopus |
| PMCID: | PMC9552147 |
| PUBMED: | 36220877 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
