Rybak Mariia Yu, Gudzera Olga I, Gorbatiuk Oksana B, Usenko Mariia O, Yarmoluk Sergiy M, Tukalo Michael A, Volynets Galyna P
Department of Protein Synthesis Enzymology, Institute of Molecular Biology and Genetics National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, Kyiv 03143, Ukraine.
Department of Cell Regulatory Mechanisms, Institute of Molecular Biology and Genetics National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, Kyiv 03143, Ukraine.
ACS Omega. 2021 Sep 16;6(38):24910-24918. doi: 10.1021/acsomega.1c03789. eCollection 2021 Sep 28.
is one of the most dangerous nosocomial pathogens which cause a wide variety of hospital-acquired infectious diseases. is considered as a superbug due to the development of multidrug resistance to all current therapeutic regimens. Therefore, the discovery of antibiotics with novel mechanisms of action to combat staphylococcal infections is of high priority for modern medicinal chemistry. Nowadays, aminoacyl-tRNA synthetases are considered as promising molecular targets for antibiotic development. In the present study, we used for the first time threonyl-tRNA synthetase (ThrRS) as a molecular target. Recombinant ThrRS was obtained in the soluble form in a sufficient amount for inhibitor screening assay. Using the molecular docking approach, we selected 180 compounds for investigation of inhibitory activity toward ThrRS. Among the tested compounds, we identified five inhibitors from different chemical classes decreasing the activity of ThrRS by more than 70% at a concentration of 100 μM. The most active compound 2,4-dibromo-6-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol has an IC value of 56.5 ± 3.5 μM. These compounds are not cytotoxic toward eukaryotic cells HEK293 (EC > 100 μM) and can be useful for further optimization and biological research.
是最危险的医院病原体之一，可引发多种医院获得性传染病。由于对所有当前治疗方案产生多药耐药性，它被视为超级细菌。因此，发现具有新型作用机制的抗生素以对抗葡萄球菌感染是现代药物化学的当务之急。如今，氨酰-tRNA合成酶被认为是抗生素开发的有前景的分子靶点。在本研究中，我们首次将苏氨酰-tRNA合成酶（ThrRS）用作分子靶点。以可溶形式获得了足够量的重组ThrRS用于抑制剂筛选试验。使用分子对接方法，我们选择了180种化合物来研究其对ThrRS的抑制活性。在测试的化合物中，我们从不同化学类别中鉴定出五种抑制剂，在100μM浓度下可使ThrRS的活性降低70%以上。活性最高的化合物2,4-二溴-6-{[4-(4-硝基苯基)-噻唑-2-基]-肼基甲基}-苯酚的IC值为56.5±3.5μM。这些化合物对真核细胞HEK293无细胞毒性（EC>100μM），可用于进一步优化和生物学研究。
