利用β-乳酸酶的聚合倾向来设计诱导酶错折的抑制剂
Ladan Khodaparast1,2, Laleh Khodaparast1,2, Guiqin Wu1,2
1Switch Laboratory, VIB Center for Brain and Disease Research, Herestraat 49, 3000, Leuven, Belgium.
Nature communications
|September 9, 2023
概括
科学家们开发了称为Pept-Ins的合成,以对抗抗生素耐药性. 这些会导致β-乳酸酶聚合,恢复抗生素对抗耐药细菌的有效性.
科学领域:
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
- 结构生物学 结构生物学
背景情况:
- 抗生素耐药性是一个日益严重的全球健康危机,由像β-lactamases这样的细菌酶驱动,这些酶会降解抗生素.
- β-乳酸酶进化以抵抗抗生素压力,通常通过其活性位点的变化.
- 一些β-乳酸酶表现出聚合倾向,这种特征在它们的进化过程中持续存在.
研究的目的:
- 开发一种新的策略来克服β-乳酸酶介导的抗生素耐药性.
- 设计合成,以向并破坏β-乳酸酶的稳定性.
- 恢复贝塔乳酸抗生素对抗耐药细菌菌株的疗效.
主要方法:
- 针对β-乳酸酶聚合的类抑制剂Pept-Ins的设计和合成.
- 利用β-乳酸酶活性位抑制剂作为分子伴侣来促进错误折叠.
- 诱导细胞内包容体的形成,以隔离β-乳酸酶.
- 测试Pept-Ins在恢复耐药临床隔离物中的β-乳糖抗生素敏感性的疗效.
主要成果:
- 酸有效地促进β-乳酸酶的错误折叠和聚合到包含体中.
- 这种有针对性的聚合恢复了对广泛的β-乳糖抗生素敏感性.
- 这种方法对具有挑战性的耐药菌株有效,包括那些具有扩展谱β-lactamases的菌株.
- 证明了利用酶聚合作为抗微生物战略的潜力.
结论:
- 通过Pept-Ins对beta-lactamase聚合的有针对性的诱导提供了一个有前途的新途径来对抗抗生素耐药性.
- 这一策略可以使细菌对现有的β-乳糖抗生素重新敏感,包括对难以治疗的变种.
- 这些发现突出了药物发现的新方法,重点是破坏抵抗机制的稳定.
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