NATURE:IspH抑制剂双管齐下杀灭革兰氏阴性菌

2020-12-26 haibei MedSci原创

这些IspH抑制剂原药直接杀灭细菌的同时,可以激活细胞毒性γδT细胞的快速免疫反应,这可能会限制抗生素耐药细菌种群的增加。

异戊二烯类化合物对所有生物体都是至关重要的,它们维持机体中膜的稳定性,并支持核心功能,如呼吸功能。IspH是异肾上腺素合成的赤藓醇磷酸甲酯途径中的一种酶,对革兰氏阴性菌、霉菌和针叶菌至关重要。它的底物,(E)-4-羟基-3-甲基-丁-2-烯焦磷酸(HMBPP),在后生生物中不能产生。在人类和其他灵长类动物,该底物在极低的浓度下可以激活细胞毒性Vγ9Vδ2 T细胞。

最近,研究人员在Nature发文,描述了一类IspH抑制剂,并通过结构引导的类似物设计,将其效力提高到纳摩尔水平。研究人员发现,将这些化合物进行修饰,做成原药递送到细菌后,可以杀死临床分离的几种耐药性细菌,包括不动杆菌属,假单胞菌,克雷伯菌,肠杆菌,弧菌,志贺菌,沙门氏菌,耶尔森菌,分枝杆菌和芽孢杆菌。此外,该原药对于哺乳动物细胞无毒。

蛋白质组分析显示,用这些原药处理的细菌与条件性IspH敲除后的细菌相似。值得注意的是,这些原药还能诱导人Vγ9Vδ2 T细胞在细菌感染的人源化小鼠模型中的扩张和激活。
因此,这些IspH抑制剂原药直接杀灭细菌的同时,可以激活细胞毒性γδT细胞的快速免疫反应,这可能会限制抗生素耐药细菌种群的增加。

 

原始出处:
Kumar Sachin Singh et al. IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance. NATURE 2020.

 

 

 

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    2021-06-04 jklm09
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    2021-05-13 liye789132251
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    2021-05-06 whmdzju
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    2021-01-12 ms7000000737941079

    厉害了

    0

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    2020-12-27 医路顺丰

    很好的文章,学习了

    0

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    2020-12-26 wxl882001

    了解

    0

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