使用晚期介导的AGLYCON输送来制造一种针对非结核菌菌的类抗生素

使用晚期介导的AGLYCON输送来制造一种针对非结核菌菌的类抗生素

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Yuka Isozaki¹, Takumi Makikawa¹, Kosuke Kimura¹

¹Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.

Science advances

|March 5, 2025

概括

一种新的候选药物KU13显示出对抗耐药性Mycobacterium avium复合体 (MAC) 肺部感染的前景. 这种新型化合物绕过了常见的抵抗机制,为这种新兴的肺病原体提供了潜在的新疗法.

科学领域:

微生物学微生物学
药用化学医学化学
结构生物学结构生物学

背景情况:

非结核菌 (NTM) 是新兴的肺病原体,Mycobacterium avium复合体 (MAC) 是肺MAC疾病的最常见原因.
阿兹胺 (AZM) 是标准的第一线治疗方法,但药物耐药性增加需要替代疗法.

研究的目的:

开发新的抗MAC药物,通过使用介导的AGLYCON输送策略来修改阿齐思罗米.
识别和表征具有针对野生类型和抗药性MAC的增强活性的化合物.

主要方法:

一个13个新型AZM衍生物 (KU01-KU13) 的图书馆是使用晚期介导的基输送合成的.
对野生型和抗宏素耐药的MAC菌株进行了抗微生物活性查.
使用冷电子显微镜来阐明化合物的结合机制.

主要成果:

与AZM相比,KU13表现出对野生类型和抗化物耐药MAC的优越抗菌活性.
低温电子显微镜显示,KU13通过一种独特的三环基团系与细菌核糖体结合,从而诱导U2847.7的基翻转.
这种新型的结合机制有可能绕过已建立的宏类抗药性途径.

结论:

KU13是一种有前途的化合物,用于开发抗宏化物耐药MAC肺部感染的治疗方法.
介导的输送策略为产生新型抗生素衍生物提供了一种可行的方法.
了解KU13活动的结构基础,可以了解如何克服菌根菌中的宏类耐药性.

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