We report the discovery of the first bacterial ribosomal RNA (rRNA) synthesis inhibitor that has specific antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). A pharmacophore model was constructed on the basis of the protein–protein interaction between essential bacterial rRNA transcription factors NusB and NusE and employed for an in silico screen to identify potential leads. One compound, (E)-2-{[(3-ethynylphenyl)imino]methyl}-4-nitrophenol (MC4), demonstrated antimicrobial activity against a panel of S. aureus strains, including MRSA, without significant toxicity to mammalian cells. MC4 resulted in a decrease in the rRNA level in bacteria, and the target specificity of MC4 was confirmed at the molecular level. Results obtained from this work validated the bacterial rRNA transcription machinery as a novel antimicrobial target. This approach may be extended to other factors in rRNA transcription, and MC4 could be applied as a chemical probe to dissect the relationship among MRSA infection, MRSA growth rate, and rRNA synthesis, in addition to its therapeutic potential.

中文翻译：

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具有抗金黄色葡萄球菌抗菌活性的核糖体RNA合成的一流抑制剂

我们报告发现了第一个细菌核糖体RNA（rRNA）合成抑制剂的发现，该抑制剂具有针对耐甲氧西林的金黄色葡萄球菌（MRSA）的特异性抗菌活性。根据必需细菌rRNA转录因子NusB和NusE之间的蛋白质-蛋白质相互作用构建了药效团模型，并将其用于计算机筛选以识别潜在的潜在顾客。一种化合物，（E）-2-{[[（3-乙炔基苯基）亚氨基]甲基} -4-硝基苯酚（MC4），表现出对一组金黄色葡萄球菌的抗菌活性。菌株，包括MRSA，对哺乳动物细胞无明显毒性。MC4导致细菌中rRNA水平降低，并且在分子水平上确定了MC4的靶标特异性。从这项工作中获得的结果证实了细菌rRNA转录机制是一种新型的抗微生物靶标。该方法可以扩展到rRNA转录中的其他因素，并且MC4可以用作化学探针来分析MRSA感染，MRSA生长速率和rRNA合成之间的关系，以及其治疗潜力。