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ABC-transporters with dual functions - detoxification and signalling by resistance modules against antimicrobial peptides

具有双重功能的 ABC 转运蛋白 - 解毒和通过抗菌肽耐药模块发出信号

基本信息

批准号：
216930737
负责人：
Professorin Dr. Susanne Gebhard
金额：
--
依托单位：
Professur für Molekulare Biotechnologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/216930737?language=en
关键词：
ABC transporters dual functions detoxification

项目摘要

A sensitive detection of the extracellular presence of antibiotics, coupled with an efficient means of signal transduction across the cell envelope, is a vital first step in mediating antimicrobial resistance. Recently, a unique group of modular systems, comprised of two-component regulatory systems (TCS) coupled to ATP-binding cassette transporters, has been identified in the response of low G+C Gram-positive bacteria to cell wall active peptide antibiotics. The best understood example for this mode of signal transduction is the BceRS-BceAB module of Bacillus subtilis, involved in bacitracin sensing and resistance. BceRS constitutes the TCS required for activation of the BceAB transporter, which in turn appears to act as an antibiotic pump. Strikingly, the transporter is also required for the detection of antimicrobial peptides by the sensor kinase BceS. Preliminary data suggest an unusual mode of signal transduction where the stimulus is detected by the transporter and communicated to the TCS via direct interactions between the transport permease and histidine kinase. The current proposal addresses central open questions regarding the molecular and biochemical mechanisms underpinning substrate binding, signal transduction and resistance by these self-sufficient detoxification modules.

对抗生素细胞外存在的灵敏检测，加上跨细胞包膜的有效信号转导手段，是介导抗微生物药物耐药性的重要第一步。最近，在低G+C革兰氏阳性菌对细胞壁活性肽类抗生素的反应中，发现了一组独特的模块化系统，包括与ATP结合盒转运蛋白偶联的双组分调节系统（TCS）。这种信号转导模式的最好理解的例子是枯草芽孢杆菌的BceRS-BceAB模块，其参与杆菌肽传感和抗性。BceRS构成激活BceAB转运蛋白所需的TCS，BceAB转运蛋白反过来似乎充当抗生素泵。引人注目的是，传感器激酶BceS检测抗菌肽也需要转运蛋白。初步数据表明，一种不寻常的信号转导模式，其中刺激被检测到的转运蛋白和沟通的TCS通过直接之间的相互作用的运输通透酶和组氨酸激酶。目前的建议解决了中央开放的问题，有关的分子和生化机制的基础基板结合，信号转导和这些自给自足的解毒模块的阻力。