Antibiotics of the ADEP and empedopeptin class - Molecular modes of action and studies on bacterial resistance

ADEP 和 empedopeptin 类抗生素 - 分子作用模式和细菌耐药性研究

• 批准号: 77063496
• 负责人: Professorin Dr. Heike Brötz-Oesterhelt
• 金额: --
• 依托单位: Lehrstuhl für Mikrobielle Wirkstoffe
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/77063496?language=en
• 关键词: Antibiotics; ADEP; empedopeptin; class; Molecular

ADEPs (an acronym for a novel class of acyldepsipeptides) and empedopeptin are natural products or derivatives thereof with promising antibacterial activity. At project start, their mechanisms of action had been poorly explored. During the previous funding period we determined the target of empedopeptin and elucidated how ADEPs dysregulate target function. It turned out that empedopeptin binds to several lipid-bound peptidoglycan precursors and prevents the activity of distinct late-stage peptidoglycan synthesis enzymes in vitro. We apply for further funding to verify the specific region of the peptidoglycan precursors recognised by empedopeptin. ADEPs act on an unprecedented target, the bacterial Clp-protease. Since project start, we performed various biochemical experiments to study the molecular nature of target inhibition and the ADEP-ClpP co-crystal structure was solved. ADEP blocks important binding sites at ClpP for regulatory partner molecules and triggers opening of the gated entry pores to the proteolytic chamber resulting in untimely degradation of flexible or nascent bacterial proteins. We also found that a preferred target is the cell division protein FtsZ. We apply for further funding to explore the molecular reason for this particular sensitivity of FtsZ and to search for further preferred degradation targets of ADEP-activated ClpP by proteomics. In addition, we plan to investigate the molecular nature of spontaneous bacterial resistance against ADEPs by analysing exemplary pathogen genera from the target level to the infection process.

ADEP（一类新的酰基缩肽的首字母缩写）和empedopeptin是具有有希望的抗菌活性的天然产物或其衍生物。在项目开始时，对它们的作用机制没有进行充分的探讨。在上一个资助期间，我们确定了empedopeptin的靶点，并阐明了ADEP如何失调靶点功能。事实证明，empedopeptin与几种脂质结合的肽聚糖前体结合，并在体外阻止不同的晚期肽聚糖合成酶的活性。我们申请进一步的资助，以验证empedopeptin识别的肽聚糖前体的特定区域。ADEP作用于一个前所未有的目标，细菌Clp-蛋白酶。自项目开始以来，我们进行了各种生化实验，以研究靶点抑制的分子性质，并解决了ADEP-ClpP共晶体结构。ADEP阻断ClpP处调节伴侣分子的重要结合位点，并触发通向蛋白水解室的门控进入孔的打开，导致柔性或新生细菌蛋白的过早降解。我们还发现，一个优选的目标是细胞分裂蛋白FtsZ。我们申请进一步的资金，以探索FtsZ这种特殊的敏感性的分子原因，并通过蛋白质组学寻找ADEP激活的ClpP的进一步优选的降解靶点。此外，我们计划通过分析从目标水平到感染过程的示例性病原体属，研究细菌对ADEP自发耐药的分子本质。

项目成果

Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ

• DOI: 10.1073/pnas.1110385108
• 发表时间: 2011-10-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Sass, Peter;Josten, Michaele;Broetz-Oesterhelt, Heike
• 通讯作者: Broetz-Oesterhelt, Heike