激活的ClpP可以杀死持久性,并消除慢性生物膜感染
B P Conlon1, E S Nakayasu, L E Fleck
1Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
Nature
|November 15, 2013
概括
慢性感染由于休眠的持续性细胞而持续存在. 用抗生素ADEP4激活ClpP蛋白酶会降解400多种蛋白质,杀死持久性蛋白质和消除生物膜,提供一种新的治疗方法.
科学领域:
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
- 分子生物学分子生物学
背景情况:
- 慢性感染的治疗具有挑战性,原因是耐受抗生素的休眠持久细胞.
- 持久性细胞是表型变体,休眠途径是多余的,使抗持久性药物开发复杂化.
- 生物膜可以保护菌体免受免疫系统的影响,因此需要抗生素来彻底消灭感染.
研究的目的:
- 为了调查是否激活休眠细胞中的目标可以杀死持久性细胞.
- 通过向持久细胞,确定乙基抗生素 (ADEP4) 是否可以根除慢性感染.
- 探索一种开发抗持久性化合物的新策略.
主要方法:
- 使用已知可以激活ClpP蛋白酶的乙基抗生素 (ADEP4).
- 评估了ADEP4激活的ClpP对休眠持久细胞的影响,包括蛋白质降解.
- 在试验室和小鼠模型中测试了ADEP4与利芬素结合对黄金葡萄球菌生物膜的疗效.
主要成果:
- 激活ADEP4的ClpP作为非特异性蛋白酶起作用,降解400多种蛋白质,并诱导持久细胞的自我消化.
- 尽管clpP无突变发生的概率很高,但ADEP4和利芬素的组合实现了Staphylococcus aureus生物膜的完全根除.
- 使用这种蛋白酶激活策略,在动物模型中成功消除了生物膜.
结论:
- 杀死休眠细胞的一般原则包括激活和破坏目标,而不是传统的抑制.
- 这些发现表明,通过开发激活蛋白酶以消除持久细胞的药物,可以为慢性感染提供可行的治疗途径.
- 这种方法通过蛋白酶激活来证明,为治疗持久性细菌感染提供了一个现实的策略.
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