探索基于氨酸的支架,用于构建细菌尿素抑制剂
Wojciech Tabor1, Aikaterini Katsogiannou2, Danai Karta2
1Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
ACS omega
|August 14, 2023
概括
研究人员开发了32种基于尿素的尿酶抑制剂. 这些化合物显示出在像Proteus mirabilis这样的细菌中控制尿解的潜力,这是一种尿路病原体.
科学领域:
- 药用化学 医学化学
- 生物化学 生物化学
- 微生物学 微生物学
背景情况:
- 尿素是诸如Proteus mirabilis之类的病原体中的关键毒性因素.
- 开发有效的尿酶抑制剂对于对抗细菌感染至关重要.
研究的目的:
- 合成和评估一个多样化的图书馆的氨酸基化合物作为潜在的尿素酶抑制剂.
- 对来自Sporosarcina pasteurii的细菌尿素酶和S. pasteurii和P. mirabilis的整个细胞的抑制活性进行研究.
主要方法:
- 合成32种氨酸衍生物,包括西米卡巴,碳水化合物,醇氨酸,醇-1-碳酸胺和二二二二二二二二.
- 用纯化的S. pasteurii尿酶进行酶动力学测定,以确定抑制常量 (Ki).
- 全细胞测试以评估对格拉姆阳性和格拉姆阴性细菌的活性.
- 分子建模研究以阐明结合相互作用.
主要成果:
- 一些化合物表现出对S. pasteurii尿酶的低微分子抑制.
- 化合物19,16和29的Ki值分别为0.39 ± 0.01μM,0.99 ± 0.04μM和2.23 ± 0.19μM.
- 分子建模表明硫离子协调与活性位点离子和结合相互作用.
- 在P. mirabilis中证明有效的尿溶解控制,其中化合物52的IC50为304±14μM.
结论:
- 合成的尿素衍生物代表了一类有前途的尿素酶抑制剂.
- 这些化合物对纯化酶和整个细菌细胞都表现出活性.
- 这些发现提供了针对依赖尿酶的细菌感染的潜在治疗策略.
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