Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36220877.
- Also identified by DOI 10.1038/s41467-022-33736-5 and PMC identifier 9552147.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Lysine-tRNA Ligase
- Mycobacterium tuberculosis
- Tuberculosis