...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of bacteriology >Novel Rapidly Diversifiable Antimicrobial RNA Polymerase Switch Region Inhibitors with Confirmed Mode of Action in Haemophilus influenzae
【24h】

Novel Rapidly Diversifiable Antimicrobial RNA Polymerase Switch Region Inhibitors with Confirmed Mode of Action in Haemophilus influenzae

机译：新型快速多样化的抗菌RNA聚合酶开关区域抑制剂具有确认的流感嗜血杆菌的作用方式。

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

A series of inhibitors with a squaramide core was synthesized following its discovery in a high-throughput screen for novel inhibitors of a transcription-coupled translation assay using Escherichia coli S30 extracts. The inhibitors were inactive when the plasmid substrate was replaced with mRNA, suggesting they interfered with transcription. This was confirmed by their inhibition of purified E. coli RNA polymerase. The series had antimicrobial activity against efflux-negative strains of E. coli and Haemophilus influenzae. Like rifampin, the squaramides preferentially inhibited synthesis of RNA and protein over fatty acids, peptidoglycan, and DNA. However, squaramide-resistant mutants were not cross-resistant to rifampin. Nine different mutations were found in parts of rpoB or rpoC that together encode the so-called switch region of RNA polymerase. This is the binding site of the natural antibiotics myxopyronin, corallopyronin, and ripostatin and the drug fidaxomicin. Computational modeling using the X-ray crystal structure of the myxopyronin-bound RNA polymerase of Thermus thermophilus suggests a binding mode of these inhibitors that is consistent with the resistance mutations. The squaramides are the first reported non-natural-product-related, rapidly diversifiable antibacterial inhibitors acting via the switch region of RNA polymerase.
机译：在高通量筛选中发现了一系列具有方酰胺核心的抑制剂后，使用大肠杆菌S30提取物对转录偶联翻译试验的新型抑制剂进行了筛选。当质粒底物被mRNA取代时，抑制剂是无活性的，表明它们干扰了转录。通过抑制纯化的大肠杆菌RNA聚合酶可以证实这一点。该系列对大肠杆菌和流感嗜血杆菌的外排阴性菌株具有抗菌活性。像利福平一样，方酸类比脂肪酸，肽聚糖和DNA优先抑制RNA和蛋白质的合成。但是，抗方酰胺的突变体对利福平没有交叉抗性。在 rpoB 或 rpoC 的部分中发现了9种不同的突变，它们共同编码了RNA聚合酶的所谓开关区域。这是天然抗生素粘菌素，珊瑚素和瑞波汀与药物非达索霉素的结合位点。使用嗜热栖热菌的粘固连蛋白结合的RNA聚合酶的X射线晶体结构进行的计算模型表明，这些抑制剂的结合模式与耐药性突变一致。方酸酰胺是最早报道的与非天然产物相关的，可快速多样化的抗菌抑制剂，它们通过RNA聚合酶的开关区域起作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号