小柯机器人

IspH抑制剂可有效杀灭革兰氏阴性菌
2020-12-25 15:04

美国威斯塔研究所Farokh Dotiwala和Joseph M. Salvino小组合作的最新研究发现IspH抑制剂可杀死革兰氏阴性菌并调动免疫清除。相关论文在线发表在2020年12月23日出版的《自然》杂志上。

研究人员发现了一类IspH抑制剂,并通过结构导向的类似物设计将其效价提高至纳摩尔水平。将这些化合物修饰做为前药处理细菌后,研究人员发现它们可以杀死几种耐多药的临床分离细菌菌株,其中包括不动杆菌属,假单胞菌属、克雷伯菌属、肠杆菌属、弧菌、志贺氏菌、沙门氏菌、耶尔森氏菌、分枝杆菌和芽孢杆菌,而对哺乳动物细胞是相对无毒的。蛋白质组学分析表明,用这些前药处理过的细菌与条件性IspH抑制后的细菌相似。值得注意的是,这些前药还可以在细菌感染的人源化小鼠模型中诱导人Vγ9Vδ2T细胞的扩增和活化。这些前药通过细胞毒性γδT细胞协同杀死细菌的同时产生快速的免疫反应,这可能会限制抗生素耐药细菌种群的增加。

据介绍,异戊二烯对所有生物的生存至关重要,它们发挥维持膜稳定性和介导诸如呼吸的核心功能。IspH是类异戊二烯合成过程中甲基赤藓糖醇磷酸途径中的一种酶,对于革兰氏阴性细菌、分枝杆菌和apicomplexans来说是必不可少的。后生动物中不产生其底物(E)-4-羟基-3-甲基-丁-2-烯基焦磷酸(HMBPP),在人和其他灵长类动物中,它以极低的浓度激活细胞毒性Vγ9Vδ2T细胞。

附:英文原文

Title: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance

Author: Kumar Sachin Singh, Rishabh Sharma, Poli Adi Narayana Reddy, Prashanthi Vonteddu, Madeline Good, Anjana Sundarrajan, Hyeree Choi, Kar Muthumani, Andrew Kossenkov, Aaron R. Goldman, Hsin-Yao Tang, Maxim Totrov, Joel Cassel, Maureen E. Murphy, Rajasekharan Somasundaram, Meenhard Herlyn, Joseph M. Salvino, Farokh Dotiwala

Issue&Volume: 2020-12-23

Abstract: Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4,5,6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.

DOI: 10.1038/s41586-020-03074-x

Source: https://www.nature.com/articles/s41586-020-03074-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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