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调整抗菌显示以识别血清活性宏环抗生素的抗生素

Justin R Randall¹, Kyra E Groover¹, Angela C O'Donnell¹

¹Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712.

bioRxiv : the preprint server for biology

|August 7, 2023

概括

研究人员开发了一种新的方法来发现新的抗生素在人体血清中有效. 这种方法确定了有前途的候选人,这些候选人是无毒的和功能性的,解决了抗菌药物发现的关键需求.

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:

抗生素耐药性需要在抗生素发现方面进行创新.
类是有希望的支架,但面临着诸如蛋白质分解不稳定性和宿主毒性等挑战.
现有的高通量查方法往往缺乏生理相关性和体内验证.

研究的目的:

调整基于功能的显示技术,用于直接在人体血清中选类宏循环.
确定影响血清活性和抗菌潜力的序列特征.
为了发现新的,无毒的类抗生素,在体内具有有效性.

主要方法:

使用适应的抗菌显示技术在人血清中选一种类宏循环库.
评估已识别的候选物的抗菌活性,血清稳定性和毒性.
评估优化类的作用机制和体内功能.

主要成果:

数十种新的宏环抗生素序列被确定.
血清活性与长度,阴离子电荷和二硫化物键数相关.
一种优化的变体证明了负外膜透,缓慢杀死细菌,哺乳动物细胞无毒性和体内有效性.

结论:

在人体血清等生理相关条件下的查对于识别功能性抗微生物来说至关重要.
优化的宏环显示治疗承诺作为新型抗生素.
这种方法提高了临床抗生素发现的效率,以对抗抗菌素耐药性.

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