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沙门氏菌类型细胞分裂激活蛋白StCAP通过影响关键分子事件来影响病变发生

Kritika Singh¹, Shubham Vashishtha¹, Ankan Chakraborty¹

¹Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi 110016, India.

ACS infectious diseases

|May 30, 2024

概括

耐多药型沙门氏菌的存活率取决于S. typhi细胞分裂激活蛋白 (StCAP). 用eltrombopag抑制StCAP提供了一种有前途的新治疗策略,用于对抗伤寒感染.

科学领域:

微生物学与传染病的研究
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

抗药多种类型的沙门氏菌为全球健康构成重大挑战.
识别保存的分子标对于开发新型抗伤寒疗法至关重要.
S. typhi细胞分裂激活蛋白 (StCAP) 是一种在 S. typhi 变种中保存的蛋白质.

研究的目的:

调查StCAP作为一种潜在的治疗点对抗沙门氏菌.
描述StCAP的DNA结合特性,并确定潜在的抑制剂.
在体外和感染宿主细胞中评估StCAP抑制的疗效.

主要方法:

在和度分析中评估StCAP的DNA结合活性.
位点定向的突变发生,以确定关键的DNA相互作用残留物 (Arg34).
检测小分子 (eltrombopag,nilotinib) 进行StCAP抑制的查.
在S. typhi培养物和受感染的THP-1衍生巨细胞 (T1Mac) 上进行抑制测定.
拉下测试用于识别StCAP相互作用蛋白 (Apaf1).
在StCAP转移的T1Mac.Mac中分析了亡和自标志物 (caspase3,LC3II) 的分析.

主要成果:

证实StCAP是一种DNA结合蛋白,Arg34对DNA相互作用至关重要.
埃尔特朗博巴格显著结合StCAP的DNA结合口袋,并抑制了S. typhi的生长 (IC50 = 38μM).
埃尔特朗博巴格在感染的巨细胞中显示出更高的疗效 (IC50 = 10μM),阻碍了殖民地形成.
StCAP与Apaf1相互作用,并影响宿主细胞亡和自途径.
通过StCAP转移的细胞显示LC3II增加和caspase3减少,表明StCAP促进宿主细胞存活.

结论:

在宿主感染期间,StCAP在Salmonella typhi的生存中发挥着至关重要的作用.
抑制StCAP,特别是用eltrombopag,是一个有前途的治疗策略.
准StCAP提供了一种新的方法来对抗多药耐药型伤寒.

关键词:

结合DNA的蛋白质可以结合DNA.这种类型的沙门氏菌.细胞分裂激活蛋白的细胞分裂激活蛋白.抑制剂抑制剂抑制剂内在的亡 (apoptosis) 是一种内在的亡.巨细胞是什么?巨细胞是什么?

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