Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS), Ufa Scientific Centre, Ufa 450054, Russia; The Federal State Unitary Enterprise Dukhov Automatics Research Institute, Moscow 127055, Russia.
Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS), Ufa Scientific Centre, Ufa 450054, Russia; Bashkir State Medical University, Ministry of Health of Russia, Ufa 450008, Russia.
Bioorg Med Chem Lett. 2021 Jul 1;43:128055. doi: 10.1016/j.bmcl.2021.128055. Epub 2021 Apr 21.
The antibacterial properties of close noscapine analogs have not been previously reported. We used our pDualrep2 double-reporter High Throughput Screening (HTS) platform to identify a series of noscapine derivatives with promising antibacterial activity. The platform is based on RPF (SOS-response/DNA damage) and Katushka2S (inhibition of translation) proteins and simultaneously provides information on antibacterial activity and the mechanism of action of small-molecule compounds against E. coli. The most potent compound exhibited an MIC of 13.5 µM(6.25 µg/ml) and a relatively low cytotoxicity against HEK293 cells (CC = 71 µM, selectivity index: ~5.5). Some compounds from this series induced average Katushka2S reporter signals, indicating inhibition of translation machinery in the bacteria; however, these compounds did not attenuate translation in vitro in a luciferase-based translation assay. The most effective compounds did not significantly arrest the mitotic cycle in HEK293 cells, in contrast to the parent compound in a flow cytometry assay. Several molecules showed activity against clinically relevant gram-negative and gram-positive bacterial strains. Compounds from the discovered series can be reasonably regarded as good templates for further development and evaluation.
先前尚未有关于近型茄呢醇类似物的抗菌特性的报道。我们使用 pDualrep2 双报告高通量筛选 (HTS) 平台来鉴定一系列具有潜在抗菌活性的茄呢醇衍生物。该平台基于 RPF（SOS 反应/DNA 损伤）和 Katushka2S（翻译抑制）蛋白，可同时提供有关小分子化合物对大肠杆菌的抗菌活性和作用机制的信息。最有效的化合物表现出 13.5 μM（6.25 μg/ml）的 MIC 和对 HEK293 细胞相对较低的细胞毒性（CC=71 μM，选择性指数：~5.5）。该系列中的一些化合物诱导平均的 Katushka2S 报告信号，表明抑制了细菌中的翻译机制；然而，这些化合物在基于荧光素酶的翻译测定中并未在体外抑制翻译。最有效的化合物在流式细胞术测定中与母体化合物相比，并未显著阻止 HEK293 细胞的有丝分裂周期。几种分子对临床相关的革兰氏阴性和革兰氏阳性细菌菌株具有活性。所发现的系列化合物可被合理地视为进一步开发和评估的良好模板。
