Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs. Academic Article uri icon

Overview

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.

authors

publication date

  • October 11, 2022

Research

keywords

  • Lysine-tRNA Ligase
  • Mycobacterium tuberculosis
  • Tuberculosis

Identity

PubMed Central ID

  • PMC388891

Scopus Document Identifier

  • 85139718046

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-33736-5

PubMed ID

  • 36220877

Additional Document Info

volume

  • 13

issue

  • 1