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对 Pseudomonas aeruginosa d-alanine-d-alanine 酶异型作为潜在的抗生素点的功能和结构比较分析

Jordan L Pederick¹, Jessica C Woolman², John B Bruning¹

¹Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences, The University of Adelaide, SA, Australia.

The FEBS journal

|August 15, 2023

概括

新的研究描述了两个酶,Pseudomonas aeruginosa D-alanine-D-alanine连酶A (PaDdlA) 和B (PaDdlB),对于细菌细胞壁的合成至关重要. 针对这两种酶提供了一个有前途的战略,用于开发针对耐药Pseudomonas aeruginosa的新型抗生素.

科学领域:

微生物学微生物学
结构生物学结构生物学
药物发现药物发现药物发现

背景情况:

Pseudomonas aeruginosa 是一个重要的医疗保健相关的病原体.
在P. aeruginosa中增加的多药耐药性 (MDR) 和广泛的耐药性 (XDR) 需要新的抗生素策略.
抑制d-alanine-d-alanine合成,对于细菌细胞壁生物合成至关重要,是一个有前途的治疗标.

研究的目的:

在功能和结构上描述P. aeruginosa,PaDdlA和PaDdlB中的两个d-alanine-d-alanine结合酶异型.
评估PaDdlA和PaDdlB作为新抗生素开发目标的潜力.
调查酶活性和抑制的结构基础.

主要方法:

进行了体外酶活性测试,以确定PaDdlA和PaDdlB的催化效率.
采用X射线晶体学,以阐明与基质和抑制剂复合的两种异构体的结构.
结构性比较分析的重点是活性部位的保护和ATP结合口袋的差异.

主要成果:

无论是PaDdlA还是PaDdlB,都有效地催化了具有相似活性的d-alanine-d-alanine生产.
模型抑制剂d-cycloserine有效地破坏了这两种酶异型的活性.
结构分析显示,PaDdlA和PaDdlB的ATP结合口袋中保留了活性点,但存在不同的化学环境.

结论:

PaDdlA和PaDdlB是针对P. aeruginosa的抗生素开发的可行目标.
开发针对PaDdlA和PaDdlB的双重抑制剂是对抗耐药菌株的有希望的战略.
结构洞察力为针对这些必需酶的合理药物设计提供了基础.

关键词:

在ATP-grasp中获取.这就是为什么我会这样做.在X射线晶体学.细胞壁生物合成细胞壁生物合成循环氨酸 (Cycloserine) 是一种氨酸.

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