Chemical Probes Unravel an Antimicrobial Defense Response Triggered by Binding of the Human Opioid Dynorphin to a Bacterial Sensor Kinase.
Chemical Probes Unravel an Antimicrobial Defense Response Triggered by Binding of the Human Opioid Dynorphin to a Bacterial Sensor Kinase.
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DOI：
10.1021/jacs.7b01072
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发表时间：
2017-04
影响因子：
15
通讯作者：
M. Wright;C. Fetzer;S. Sieber
中科院分区：
文献类型：
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作者：
M. Wright;C. Fetzer;S. Sieber
宿主-微生物通过小分子信号的交流对于共生和致病关系都很重要，但在分子水平上往往知之甚少。在宿主应激条件下，人类阿片肽啡肽水平升高，通过未知途径触发机会致病菌铜绿假单胞菌的毒力。在这里，我们应用多层化学生物学策略来解开这个假定的王国间信号的作用模式。我们设计并应用了动力啡激发的光亲和探针，通过化学蛋白质组学揭示了活菌中肽的蛋白靶点。ParS是一种很大程度上未被表征的双组分系统膜传感器，被认为是最有希望的成功。随后的全蛋白质组研究表明，dynorphin（1-13）在假单胞菌中诱导抗菌肽样反应，并特异性上调膜防御机制。在parS突变体中没有观察到这种反应，它更容易受到强啡诱导的毒性。因此，铜绿假单胞菌利用ParS感知机制来保护自己免受宿主对肌啡肽作为信号的响应。本研究强调，界间交流不仅是诱导铜绿假单胞菌毒力的潜在基本策略，而且也是在宿主的敌对环境中保持生存能力的潜在基本策略。
Host-microbe communication via small molecule signals is important for both symbiotic and pathogenic relationships, but is often poorly understood at the molecular level. Under conditions of host stress, levels of the human opioid peptide dynorphin are elevated, triggering virulence in the opportunistic pathogenic bacterium Pseudomonas aeruginosa via an unknown pathway. Here we apply a multilayered chemical biology strategy to unravel the mode of action of this putative interkingdom signal. We designed and applied dynorphin-inspired photoaffinity probes to reveal the protein targets of the peptide in live bacteria via chemical proteomics. ParS, a largely uncharacterized membrane sensor of a two-component system, was identified as the most promising hit. Subsequent full proteome studies revealed that dynorphin(1-13) induces an antimicrobial peptide-like response in Pseudomonas, with specific upregulation of membrane defense mechanisms. No such response was observed in a parS mutant, which was more susceptible to dynorphin-induced toxicity. Thus, P. aeruginosa exploits the ParS sensing machinery to defend itself against the host in response to dynorphin as a signal. This study highlights interkingdom communication as a potential essential strategy not only for induction of P. aeruginosa virulence but also for maintaining viability in the hostile environment of the host.