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针对ArnA脱酶的合规变化,用于选择性抑制聚米克辛耐药性

Megan E Mitchell¹, Petia Z Gatzeva-Topalova¹, Austin D Bargmann²

¹Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado 80309, United States.

|July 6, 2023

概括

通过抑制ArnA酶,可以克服细菌中的多素耐药性. 在结合UDP-葡萄糖酸时,ArnA的关键形状变化对其活性至关重要,为新抗生素开发提供了目标.

科学领域:

结构生物学结构生物学
微生物学微生物学
药物发现药物发现药物发现

背景情况:

聚米克辛是对抗多药耐药格兰氏阴性细菌的关键的最后手段抗生素.
细菌对多素的耐药性源于脂质A被4-氨基-4-脱氧-l-氨酸 (Ara4N) 的修饰.
抑制Ara4N修饰通路是恢复多素疗效的有希望的策略.

研究的目的:

阐明UDP-葡萄糖酸 (UDP-GlcA) 通过ArnA脱酶域 (ArnA_DH) 结合的结构和机制基础.
为了确定选择性抑制细菌耐药性途径的潜在目标.

主要方法:

沙门氏菌的X射线晶体学Entericaserovar typhimurium ArnA复合与UDP-GlcA. 这是一个复杂的UDP-GlcA.
结构和序列分析以比较细菌和人类的ArnA_DH同类.
配体结合测定,酶活性测定和位点定向突变发生 (N492A).

主要成果:

结合UDP-GlcA诱导了细菌ArnA_DH的保存形状变化,这种变化在人类同类中不存在.
这种形状变化对于NAD+结合和随后的催化是必不可少的.
UDP-GlcA的6'碳酸盐对于诱导形状变化至关重要,尿素单酸盐部分对结合能量有显著的贡献.

结论:

在ArnA_DH中,UDP-GlcA诱导的构造变化是细菌多菌素耐药性的关键机制步骤.
ArnA_DH代表了开发新型抑制剂以对抗抗生素耐药性的潜在选择性标.
了解基质结合相互作用为合理的药物设计提供了基础.

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