通过利用合成杀伤性快速发现抑制剂
Jacob D Muscato1, Heidi G Morris1, Aaron Mychack1
1Department of Microbiology, Harvard University, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Journal of the American Chemical Society
|February 16, 2022
概括
合成的致命性使得药物发现更加有效. 研究人员发现了两种向黄金葡萄球菌 (Staphylococcus aureus) 脂质醇酸 (LTA) 生物合成的化合物,恢复了耐药菌株的抗生素敏感性.
科学领域:
- 微生物学
- 药物发现
- 合成杀伤性
背景情况:
- 合成致死性是一种强大的策略,用于识别基本的基因相互作用和潜在的药物标.
- 识别抑制重要细菌通路的化合物对于对抗抗生素耐药性至关重要.
研究的目的:
- 为了利用合成的致死性,发现新型的Staphylococcus aureus lipoteichoic acid (LTA) 生物合成抑制剂.
- 识别针对GLTP的化合物,这对于LTA组装至关重要.
主要方法:
- 对大约23万种化合物进行差异生长选.
- 使用合成致死性原理来识别选择性抑制蛋白质的化合物.
- 对UgtP的测试化合物活性及其在LTA生物合成中的作用.
主要成果:
- 从选库中确定了两个新化合物作为LTA生物合成的唯一抑制剂.
- 发现这两种化合物都抑制了UgtP糖转移酶.
- 抑制剂恢复了对甲素高度耐药的金黄色葡萄球菌菌株 (MRSA) 的敏感性.
结论:
- 利用合成致死性的查对于发现特定途径的抑制剂是非常有效的.
- 已发现的UgtP抑制剂代表了对抗MRSA感染的有希望的新途径.
- 这种方法广泛适用于细菌和真核生物药物发现.
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