Identification of novel Mycobacterium tuberculosis leucyl-tRNA synthetase inhibitors with antibacterial activity.

BACKGROUND: Tuberculosis has become the world's most lethal infectious disease. A major challenge in treating tuberculosis is the multidrug resistance of Mycobacterium tuberculosis to existing antibiotics. Therefore, there is an urgent need to discover new antituberculosis agents with unexploited mechanisms of action. The aim of the work was to develop inhibitors of mycobacterial leucyl-tRNA synthetase (LeuRS) with antibacterial activity. MATERIALS AND METHODS: The virtual screening of compound collection containing about 250,000 ligands into aminoacyl-adenylate binding site of M. tuberculosis LeuRS was performed with AutoDock 4.2 software. The inhibitory activity of compounds toward recombinant LeuRS was studied in aminoacylation assay using (14)C-labeled L-leucine. Antibacterial activity was investigated toward M. tuberculosis H37Rv strain under four different conditions. RESULTS: According to the data of biochemical screening, we have found M. tuberculosis LeuRS inhibitors among N-(5-Benzyl-thiazol-2-yl)-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide deivatives, which decrease enzyme activity with IC(50) values in micromolar range. The most promising compound, N-(5-Benzyl-thiazol-2-yl)-2-[4-(4-methoxy-phenyl)-1H-tetrazol-5-ylsulfanyl]-acetamide, reveals potent antibacterial activity with the best minimum inhibitory concentration (MIC) value of 4.7 µM. CONCLUSION: N-(5-Benzyl-thiazol-2-yl)-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide scaffold can be valuable for further biological research and chemical optimization.