泰洛米的生物合成研究揭示了具有增强活性的新脂
Chengzhang Fu1, Lena Keller1,2, Armin Bauer
1†Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University, Building C 2.3, 66123, Saarbrücken, Germany.
Journal of the American Chemical Society
|June 5, 2015
概括
研究人员特征了端粒素 (TEM) 生物合成基因集群,使新型抗生素类型的途径工程成为可能. 他们发现了一种新型的前体脱机制,并确定了对抗多药耐药细菌具有强效活性的TEM前体.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 端粒素 (TEM) 是一种循环脱类抗生素,有效对抗阳性细菌.
- 了解TEM生物合成对于开发新的类似物和改善生产至关重要.
研究的目的:
- 描述TEM生物合成基因集群用于途径工程.
- 为了研究TEM前体脱机制.
- 探索用于制药应用的新型TEM衍生品.
主要方法:
- 在Streptomyces albus中基因集群的表征和异质表达.
- 氧化酶和P450单氧化酶基因的框架内基因缺失.
- 在体内对Tem25酶进行基因失活和体内生化表征.
- 脂前体的结构阐明和脱研究.
主要成果:
- 一个80.5kb的TEM生物合成基因集群与34个基因被确定和异质表达.
- 删除突变产生了新的TEM衍生物,识别了负责氨基酸修饰的基酶和P450基因.
- 一种涉及Tem25的新型前体脱氧化机制被阐明,揭示了产生端粒素和6 - 甲基酸的脂前体.
- TEM前体和半合成衍生品显示出对抗多药耐药性格拉姆阳性病原体的快速杀菌活性.
结论:
- 这种特征的TEM基因集群为新型类型的生物合成工程提供了便利.
- 已识别的脱基化途径和前体为提洛米辛优化提供了新的途径.
- 新型TEM衍生物显示出对抗多药耐药性格兰美阳性感染的前景.
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