克服Vat耐药性的A组合成链杆菌抗生素
Qi Li1, Jenna Pellegrino2, D John Lee2
1Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
Nature
|September 24, 2020
概括
研究人员设计了一种新型A组链杆菌抗生素来对抗细菌耐药性. 这些新化合物对抗抗性黄金葡萄球菌有前途,并可能使现有的抗生素类恢复活力.
科学领域:
- 微生物学
- 药物发现
- 结构生物学
背景情况:
- 自然产品是抗生素的主要来源,
- 弗吉尼亚氨酸乙转移酶 (Vat) 赋予了对强效抗生素的抗性.
- 修改复杂的链条蛋白结构以克服Vat的耐药性是一项挑战.
研究的目的:
- 设计和合成具有结构可变性的新型A组链条蛋白类型.
- 评估这些类似物对抗耐药菌株的抗菌活性.
- 了解这些类似物与细菌核糖体的结合相互作用.
主要方法:
- 合理的设计和模块化化学合成的链条蛋白类型.
- 高分辨率的冷电子显微镜和基于力场的精细化.
- 在体外乙化试验和体内小鼠感染模型.
主要成果:
- 合成和评估了八种结构上不同的类似物.
- 低温EM检测显示了核糖体内的结合相互作用,包括基tRNA结合部位和新生的退出道.
- 一种类型在小鼠感染模型中表现出对抗抗性黄金葡萄球菌的强烈活性,降低了乙化和有效性.
结论:
- 合理的设计和合成可以克服抗生素的自然抵抗机制.
- 可以开发新型链杆菌胺类药物来对抗Vat介导的耐药性.
- 这种方法为面对抗药性挑战的抗生素类别提供了振兴的策略.
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