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Information × Registration Number 0220U104259, 0120U104795 , R & D reports Title Site-directed mutagenesis as a novel strategy to investigate and overcome Mycobacterium tuberculosis antibiotic resistance popup.stage_title Head Yarmoliuk Serhii M., Доктор хімічних наук Registration Date 15-12-2020 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description2   We have performed molecular docking of compound collection containing more than 150,000 ligands into the aminoacyl adenylate-binding sites of M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). According to the results of virtual screenings we have selected 115 compounds for investigation of their inhibitory activity toward mycobacterial LeuRS and MetRS. Recombinant M. tuberculosis LeuRS and MetRS have been obtained in Escherichia coli in a soluble form. Selected compounds have been tested for inhibitory activity against LeuRS and MetRS using aminoacylation assay. According to the results of screening, 9 novel inhibitors of M. tuberculosis MetRS and 7 inhibitors of LeuRS were identified. The derivatives of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole were investigated for inhibitory activity toward mycobacterial LeuRS and MetRS, as well as for antibacterial activity toward a panel of M. tuberculosis pathogenic strains. In vitro studies revealed 10 compounds inhibiting MetRS and 3 compounds decreasing LeuRS activity by more than 50% at a concentration of 100 µM. According to antibacterial screening, we have identified 4 compounds inhibiting the growth of M. tuberculosis cells in the concentration range from 2 to 20 mg/l. Among the compounds possessing antibacterial activity, only one compound – 3-(5-Chloro-2-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine has significant inhibitory activity toward M. tuberculosis MetRS. This compound is non cytotoxic toward HEK293 and HepG2 cells (IC50 > 50 µM) and may be a promising candidate for further chemical optimization and biological research. Product Description popup.authors popup.nrat_date 2020-12-15 Close