在Mycobacterium tuberculosis中, siderophore 分泌和药物流出之间有着复杂的联系
Virginia Meikle1, Lei Zhang1, Michael Niederweis1
1Department of Microbiology, University of Alabama at Birmingham , Birmingham, Alabama, USA.
Antimicrobial agents and chemotherapy
|September 7, 2023
概括
针对Mycobacterium tuberculosis中的 siderophore 分泌物增加了对关键结核病药物的敏感性. 破坏这些流量系统为对抗耐药结核病提供了一个新的策略.
科学领域:
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
- 分子生物学分子生物学
背景情况:
- 耐药结核病 (TB) 构成了全球健康威胁,药物排放机制导致治疗失败.
- MmpS4-MmpL4和MmpS5-MmpL5系统对于Mycobacterium tuberculosis中 siderophore分泌至关重要,影响其生存和毒性.
- 无活化 siderophore 分泌物对 M. tuberculosis 有毒,特别是在铁含量低的条件下.
研究的目的:
- 研究 siderophore 分泌系统 (MmpS4-MmpL4 和 MmpS5-MmpL5) 在 Mycobacterium 结核病耐药性的作用.
- 确定开发抗药性结核病的双重作用药物的潜在新目标.
主要方法:
- 基因删除和补充实验是在Mycobacterium结核病突变菌上进行的.
- 评估了突变菌株对关键结核病药物的敏感性,包括贝达奎林,克洛法齐明和利法布丁.
- 还研究了周等离子体Rv0455c蛋白在药物敏感性中的作用.
主要成果:
- 缺乏MmpS4-MmpL4或MmpS5-MmpL5组件的突变体对贝达奎林,克洛法齐明和利法布丁的敏感性增加.
- 虽然MmpL4和MmpL5载体在 siderophore 和药物分泌中具有冗余的作用,但MmpS5-MmpL5在恢复药物流量方面比MmpS4-MmpL4更有效.
- 删除Rv0455c蛋白也导致对这些结核病药物的敏感性增加.
结论:
- MmpS4-MmpL4和MmpS5-MmpL5 siderophore分泌系统与Mycobacterium结核病对重要结核病药物的耐药性有关.
- 阻断 siderophore 分泌是一种有前途的策略,用于开发新型双功能的结核病药物,既可以抑制细菌的存活,也可以提高现有治疗的疗效.
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