Mycobacterium tuberculosis leucyl-tRNA synthetase docking results

<b>Background.</b> Tuberculosis has become the world's most lethal infectious disease. A major challenge in treating tuberculosis is the multidrug resistance of <i>Mycobacterium tuberculosis</i> 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. <b>Materials and Methods. </b>The virtual screening of compound collection containing about 250,000 ligands into aminoacyl-adenylate binding site of <i>M. tuberculosis</i> LeuRS was performed with AutoDock 4.2 software. The inhibitory activity of compounds toward recombinant LeuRS was studied in aminoacylation assay using ¹⁴C-labeled L-leucine. Antibacterial activity was investigated toward <i>M. tuberculosis</i> H37Rv strain under four different conditions. <b>Results. </b>According to the data of biochemical screening we have found <i>M. tuberculosis</i> LeuRS inhibitors among N-(5-Benzyl-thiazol-2-yl)-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide deivatives which decrease enzyme activity with IC₅₀ 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. <b>Conclusion.</b> 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.