在结构指导下发现了新型泛金属β-乳糖酶抑制剂,改善了对格兰氏阴性细菌细胞的透
Shuzhi Dong1, Zhiqiang Zhao1, Haiqun Tang1
1Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Journal of medicinal chemistry
|February 22, 2024
概括
新药发现工作的重点是对抗耐β-乳酸抗生素耐药的格拉姆阴性细菌感染. 针对金属β-乳酸酶,特别是VIM-1和VIM-2,对于有效的治疗策略至关重要.
科学领域:
- 药用化学 医学化学
- 微生物学 微生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- β-乳酸胺 (BL) 和β-乳酸酶抑制剂的组合已在临床上得到验证,可以预防BL耐药性.
- 格拉姆阴性 (GN) 细菌中的金属β-乳酸酶 (例如IMP,VIM,NDM) 具有显著的未满足的医疗需求.
- 之前的工作确定了IMP,VIM和NDM家族的泛抑制剂.
研究的目的:
- 为了提高β-乳酸酶抑制剂的格兰阴性 (GN) 覆盖率,与伊米和relebactam结合使用.
- 通过基于结构和属性的优化,解决 GN 细胞透和流出方面的挑战.
- 确定广泛的GN抗菌活性的主要目标.
主要方法:
- 基于药物候选物的结构和属性优化.
- 对金属β-乳糖酶家族 (IMP,VIM,NDM) 抑制剂疗效的评估.
- 评估GN细菌覆盖面,包括产生VIM的P. aeruginosa.
- 选择化合物的药理动力学和非临床安全性概况.
主要成果:
- 优化工作在与伊米和relebactam结合时增强了GN覆盖范围.
- 发现抑制VIM-1和VIM-2等位基因对广泛的GN活性至关重要.
- 化合物显示出对产生VIM的P. aeruginosa*的潜在作用.
结论:
- 药物发现运动成功地改善了β-乳糖酶抑制剂的GN覆盖率.
- 向VIM等位基因对于治疗由VIM产生GN细菌引起的感染至关重要.
- 这些发现为识别耐药感染的临床前候选人提供了基础.
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