调节分枝杆菌包膜的完整性,实现苯并噻唑类抗生素的协同作用。

IF 3.3 2区 生物学 Q1 BIOLOGY
Life Science Alliance Pub Date : 2024-05-14 Print Date: 2024-07-01 DOI:10.26508/lsa.202302509
Eva Habjan, Alexander Lepioshkin, Vicky Charitou, Anna Egorova, Elena Kazakova, Vien Qt Ho, Wilbert Bitter, Vadim Makarov, Alexander Speer
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引用次数: 0

摘要

由于分枝杆菌的细胞包膜具有不透性,其固有的抗生素耐药性阻碍了有效结核病药物的开发。我们利用苯并噻唑化合物,旨在提高分枝杆菌细胞包膜的通透性,并削弱作为结核分枝杆菌模型的马氏分枝杆菌的防御能力。它在M. marinum-斑马鱼胚胎感染模型和结核杆菌感染巨噬细胞中也显示出疗效。值得注意的是,BT-08 能与万古霉素和利福平等既有抗生素产生协同作用。随后的药物化学优化产生了 BT-37,这是一种无毒且药效更强的衍生物,也能提高溴化乙锭的吸收,并在受感染的斑马鱼胚胎中保持与利福平的协同作用。对 BT-37 产生抗性的 M. marinum 突变体揭示了 MMAR_0407 (Rv0164) 是分子靶点,并且该靶点在观察到的协同作用和渗透性中发挥了作用。这项研究介绍了针对一种新的分枝杆菌易感性的新型化合物,并强调了它们与现有抗生素的合作与协同作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles.

Developing effective tuberculosis drugs is hindered by mycobacteria's intrinsic antibiotic resistance because of their impermeable cell envelope. Using benzothiazole compounds, we aimed to increase mycobacterial cell envelope permeability and weaken the defenses of Mycobacterium marinum, serving as a model for Mycobacterium tuberculosis Initial hit, BT-08, significantly boosted ethidium bromide uptake, indicating enhanced membrane permeability. It also demonstrated efficacy in the M. marinum-zebrafish embryo infection model and M. tuberculosis-infected macrophages. Notably, BT-08 synergized with established antibiotics, including vancomycin and rifampicin. Subsequent medicinal chemistry optimization led to BT-37, a non-toxic and more potent derivative, also enhancing ethidium bromide uptake and maintaining synergy with rifampicin in infected zebrafish embryos. Mutants of M. marinum resistant to BT-37 revealed that MMAR_0407 (Rv0164) is the molecular target and that this target plays a role in the observed synergy and permeability. This study introduces novel compounds targeting a new mycobacterial vulnerability and highlights their cooperative and synergistic interactions with existing antibiotics.

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来源期刊
Life Science Alliance
Life Science Alliance Agricultural and Biological Sciences-Plant Science
CiteScore
5.80
自引率
2.30%
发文量
241
审稿时长
10 weeks
期刊介绍: Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.
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