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

TitleLysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.
Publication TypeJournal Article
Year of Publication2022
AuthorsGreen SR, Davis SH, Damerow S, Engelhart CA, Mathieson M, Baragaña B, Robinson DA, Tamjar J, Dawson A, Tamaki FK, Buchanan KI, Post J, Dowers K, Shepherd SM, Jansen C, Zuccotto F, Gilbert IH, Epemolu O, Riley J, Stojanovski L, Osuna-Cabello M, Pérez-Herrán E, Rebollo MJosé, López LGuijarro, Castro PCasado, Camino I, Kim HC, Bean JM, Nahiyaan N, Rhee KY, Wang Q, Tan VY, Boshoff HIM, Converse PJ, Li S-Y, Chang YS, Fotouhi N, Upton AM, Nuermberger EL, Schnappinger D, Read KD, Encinas L, Bates RH, Wyatt PG, Cleghorn LAT
JournalNat Commun
Volume13
Issue1
Pagination5992
Date Published2022 Oct 11
ISSN2041-1723
KeywordsAnimals, Lysine-tRNA Ligase, Mice, Mycobacterium tuberculosis, Tuberculosis
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.

DOI10.1038/s41467-022-33736-5
Alternate JournalNat Commun
PubMed ID36220877
PubMed Central IDPMC9552147
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
100195/Z/12/Z / WT_ / Wellcome Trust / United Kingdom

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