Identification of novel 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 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 LeuRS was performed with AutoDock 4.2 software. The inhibitory activity of compounds toward recombinant LeuRS was studied in aminoacylation assay using C-labeled L-leucine. Antibacterial activity was investigated toward H37Rv strain under four different conditions.

RESULTS

According to the data of biochemical screening, we have found LeuRS inhibitors among -(5-Benzyl-thiazol-2-yl)-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide deivatives, which decrease enzyme activity with IC 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

-(5-Benzyl-thiazol-2-yl)-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide scaffold can be valuable for further biological research and chemical optimization.