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验证aminodeoxychorismate synthase和anthranilate synthase作为双特异性抗生素的新型标,可以抑制保存的蛋白质-蛋白质相互作用

Franziska Jasmin Funke¹, Sandra Schlee¹, Reinhard Sterner¹

¹Institute of Biophysics and Physical Biochemistry, Regensburg Center for Biochemistry, University of Regensburg, Regensburg, Germany.

Applied and environmental microbiology

|May 3, 2024

概括

针对重要细菌酶的新型抗菌策略对抗多耐药性病原体有希望. 抑制叶酸和酸生物合成途径中的蛋白质-蛋白质相互作用提供了一种强大的方法来对抗抗生素耐药性.

科学领域:

微生物学微生物学
生物化学生物化学
药物发现药物发现药物发现

背景情况:

多抗性细菌对现代医学构成重大威胁.
新型抗菌点对于开发针对新兴耐药性的强有力的治疗方法至关重要.
在重要的代谢途径中准保存的蛋白质-蛋白质相互作用提供了一个有希望的策略.

研究的目的:

识别和验证具有高强度的新型抗菌标,对抗抗性介导突变.
研究一种双特异性抑制剂的潜力,该抑制剂针对aminodeoxychorismate合成酶和antranilate合成酶中保存的子单元接口.
为了验证这些标对于它们在核糖体中叶酸和酸盐生物合成中的作用.

主要方法:

在实验室中对谷氨胺胺转移酶复合体中保存的接口热点残留物进行表征.
基因组修饰的大肠杆菌菌株的生成与中断的子单元协会.
在体内评估细菌生长抑制和细菌静止效应.

主要成果:

两个保存的接口热点残留物被证实对子单元协会和酶活性至关重要.
基因组修改的大肠杆菌菌株由于叶酸和酸盐生物合成中断,表现出大幅减缓的生长.
即使在人体血中也观察到细菌静止效应,这表明疗效独立于宿主代谢物.

结论:

针对aminodeoxychorismate synthase和anthranilate synthase中的保护蛋白-蛋白相互作用是开发新型抗生素的可行策略.
针对这两种酶的双特异性抑制剂有可能具有广泛的疗效和增加抗生素耐药性的弹性.
这种方法提供了一个强大的解决方案,以对抗多抗性细菌日益增长的威胁.

关键词:

抗生素耐药性抗生素耐药性抗生素标验证的验证方法酶复合体是一种复杂的酶.谷氨胺胺转移酶的作用.蛋白质与蛋白质的相互作用

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