基于结构优化非β-乳糖的结果在抑制剂,不调节β-乳糖酶表达在细胞培养中的上调抑制剂
Donatella Tondi1, Federica Morandi, Richard Bonnet
1Department of Pharmaceutical Chemistry, University of California-San Francisco, 600 16th Street, San Francisco, CA 94143-2240, USA.
Journal of the American Chemical Society
|March 31, 2005
概括
新型非β-乳糖抑制剂对抗细菌对抗生素的耐药性. 化合物10显著增强AmpCβ-乳糖酶抑制,在不调节酶表达的情况下逆转病原体对塞夫塔齐的耐药性.
科学领域:
- 微生物学和生物化学
- 药物发现和开发 药物发现和开发
- 结构生物学 结构生物学
背景情况:
- 细菌β-乳糖酶酶是对β-乳糖抗生素 (如青素和头素) 的抗药性的主要原因.
- 现有的β-乳糖酶抑制剂通常与抗生素具有结构相似性,可能导致补偿性耐药机制.
- 对于新型的非β-乳糖抑制剂来克服广泛存在的抗生素耐药性的需求非常严重.
研究的目的:
- 设计和合成新的AmpCβ-lactamase的非β-乳糖酶抑制剂.
- 通过结构修改,改善先前识别的抑制剂 (化合物1) 的适度活性.
- 阐明增强抑制活性的结构基础,了解作用机制.
主要方法:
- 基于结构的药物设计,使用AmpC/compound 1复合物的X射线晶体结构.
- 合成14种类型的化合物 1.化合物的类型.
- 酶抑制试验用于确定抑制常量 (K(i)).
- 进行X射线晶体学以确定与新型抑制剂复合的AmpC的结构.
- 基于细胞的测试,以评估抑制剂在逆转抗生素耐药性的有效性.
主要成果:
- 与化合物1相比,新型模拟物化合物10在抑制活性 (K(i) = 1微米) 中表现出26倍的改善.
- X射线结晶学揭示了化合物10与AmpC的增强结合的结构基础.
- 化合物10有效地在细胞培养中表达AmpC的细菌病原体中逆转了对塞夫塔齐的耐药性.
- 与β-乳糖酶抑制剂不同,化合物10没有诱导β-乳糖酶的表达.
结论:
- 设计的非β-乳酸胺抑制剂,化合物10代表了对抗AMPC介导的抗生素耐药性的重大进展.
- 结构性见解引导了开发一种具有有利作用机制的强效抑制剂.
- 化合物10表明作为治疗剂对抗耐素的细菌病原体具有前途.
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