简单的二次氨基因通过高度选择性地结合到氨基-tRNA合成酶来抑制格拉姆阴性细菌的生长
Vadim Baidin1, Tristan W Owens1, Michael B Lazarus2
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Journal of the American Chemical Society
|January 7, 2021
概括
一种新的二次氨基抗生素通过抑制PheRS酶来选择性地向阴性细菌. 这一发现为开发抗药性格拉姆阴性感染的新疗法提供了有前途的支架.
科学领域:
- 医学化学
- 微生物学
- 结构生物学
背景情况:
- 耐药格兰氏阴性感染对全球健康构成重大威胁,需要发现新型抗生素.
- 现有的治疗选择有限, 开发新抗菌剂对抗这些病原体是具有挑战性的.
研究的目的:
- 识别和描述具有对抗药物耐药性格拉姆阴性细菌的新化合物.
- 阐明一种新发现的抗生素支架的作用机制和选择性.
主要方法:
- 基于细胞的查被用于识别格拉姆阴性细菌的生长抑制剂.
- 对抗性突变进行了测绘以确定向酶,随后进行了生物化学测试.
- 确定了与抑制剂复合的目标酶的晶体结构.
- 用生物信息分析和突变发生来了解选择性.
主要成果:
- 一种简单的二次氨基被发现可以抑制大肠杆菌和宝曼菌的生长,但不能抑制细菌.
- 对氨基酸tRNA合成酶PheRS进行映射的抗性突变,确认它是标.
- 结构和生化研究显示该化合物通过诱导特定的疏水口袋来选择性抑制格兰负PheRS.
- 该化合物对野生型格兰氏阴性病原体表现出活性,对哺乳动物细胞无细胞毒性.
结论:
- 一种新型的二次氨基基基架选择性地向了阴性PheRS,为新的抗生素开发提供了有前途的起点.
- 该化合物的选择性是基于其诱导格拉姆阴性PheRS中独特的疏水口袋的能力.
- 这种支架有可能用于抗生素组合治疗具有挑战性的格拉姆阴性感染.
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