针对Helicobacter pylori的新抗生素候选物
Shanzhi Wang1, Scott A Cameron1, Keith Clinch2
1Department of Biochemistry, Albert Einstein College of Medicine , New York, New York, 10461, United States.
Journal of the American Chemical Society
|October 24, 2015
概括
针对Helicobacter pylori (H. pylori) 的新药候选物显示出强大的抑制和细胞透. 这些新型化合物对H.pylori有效,为现有抗生素提供了有希望的替代品.
科学领域:
- 微生物学
- 药物发现
- 生物化学
背景情况:
- 杆菌 (H. pylori) 感染影响全球50%以上的人口,导致胃并增加胃癌的风险.
- 在H. pylori中抗生素耐药性需要针对独特细菌途径的新疗法.
- 杆菌利用了一种不寻常的menaquinone生物合成途径,涉及5'-甲基腺/S-adenosylhomocysteine核酶 (MTAN).
研究的目的:
- 确定和验证具有作为新抗生素潜力的新型H. pylori MTAN抑制剂.
- 探索MTAN抑制和H. pylori生长抑制的结构性支架.
- 评估MTAN抑制剂透格兰阴性H. pylori细胞膜的能力.
主要方法:
- 合成和表征十六个过渡状态的同类抑制剂 H. pylori MTAN.
- 确定抑制剂与MTAN的结合亲和力 (解离常数).
- 对H. pylori生长抑制 (IC90值) 和细胞透的评估.
- 在MTAN活性部位内阐明抑制剂结合模式的X射线晶体学.
主要成果:
- 十六种MTAN抑制剂的分离常数为50 pM或以下,表明结合密度很高.
- 其中10种抑制剂有效地阻止了H. pylori的生长,其IC90值低于0. 01μg/ ml.
- 抑制剂表现出强烈的活性和细胞透,超过常见的H. pylori抗生素的16-2000倍.
结论:
- MTAN是H.pylori的有效药物标.
- 新的MTAN过渡状态模拟抑制剂显示出作为新的H. pylori抗生素的巨大潜力.
- 这些化合物提供了对当前治疗的有希望的替代品,因为它们的效力和克服抗药机制的能力.
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