QStatin，弧菌种群感应的选择性抑制剂。,mBio

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QStatin，弧菌种群感应的选择性抑制剂。
mBio ( IF 5.1 ) Pub Date : 2018-01-30 , DOI: 10.1128/mbio.02262-17
Byoung Sik Kim _{1,

2} , Song Yee Jang ₂ , Ye-Ji Bang ₁ , Jungwon Hwang ₂ , Youngwon Koo ₃ , Kyung Ku Jang ₁ , Dongyeol Lim ₃ , Myung Hee Kim ₄ , Sang Ho Choi ₅

Affiliation

致病性弧菌会导致水产养殖中饲养的多种海洋动物患病。由于它们在海洋环境中的发病机制、持久性和生存受到群体感应 (QS) 的调节，因此 QS 干扰作为在水生环境中控制这些细菌的一种手段而引起了人们的关注。已经报道了一些弧菌 QS 抑制剂，但缺乏详细的分子机制。在这里，我们确定了一种新型、有效和选择性的弧菌 QS 抑制剂，命名为 QStatin [1-(5-溴噻吩-2-磺酰基)-1H-吡唑]，它影响哈维弧菌 LuxR 同源物，即保存完好的主转录调节因子弧菌属中的 QS。晶体学和生化分析表明，QStatin 与 SmcR 中假定的配体结合口袋紧密结合，SmcR 是创伤弧菌中的 LuxR 同系物，并改变蛋白质的柔韧性，从而改变其转录调节活性。转录组分析表明，QStatin 导致 SmcR 功能障碍，影响毒力、运动/趋化性和生物膜动力学所需的 SmcR 调节子的表达。值得注意的是，QStatin 减弱了各种弧菌物种中具有代表性的 QS 调节表型，包括对丰年虾（Artemia franciscana）的毒力。总之，这些结果为有效、可持续的 QS 抑制剂的作用机制提供了分子见解，这种抑制剂比其他抗菌剂更不容易产生耐药性，并且有助于控制水产养殖中弧菌的毒力。重要水产养殖的产量，例如对虾孵化场，受弧菌病的影响很大，由致病性弧菌感染引起的疾病。由于细菌细胞间通讯（称为群体感应 (QS)）调节海洋环境中弧菌的发病机制，因此 QS 抑制剂作为水生环境中传统抗生素的替代品引起了人们的关注。在这里，我们使用基于目标的高通量筛选来鉴定 QStatin，它是 V. harveyi LuxR 同源物的有效选择性抑制剂，是弧菌物种中保存完好的主要 QS 调节剂。结构和生化分析表明，QStatin 与 SmcR（创伤弧菌中的 LuxR 同系物）上假定的配体结合口袋紧密结合，并影响 QS 调节基因的表达。值得注意的是，QStatin 减弱了各种弧菌物种中多种 QS 调节的表型，包括对盐水虾的发病机制，对细菌活力没有影响。总之，结果表明 QStatin 可能是一种可用于水产养殖的可持续抗弧菌剂。

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QStatin, a Selective Inhibitor of Quorum Sensing in Vibrio Species.

Pathogenic Vibrio species cause diseases in diverse marine animals reared in aquaculture. Since their pathogenesis, persistence, and survival in marine environments are regulated by quorum sensing (QS), QS interference has attracted attention as a means to control these bacteria in aquatic settings. A few QS inhibitors of Vibrio species have been reported, but detailed molecular mechanisms are lacking. Here, we identified a novel, potent, and selective Vibrio QS inhibitor, named QStatin [1-(5-bromothiophene-2-sulfonyl)-1H-pyrazole], which affects Vibrio harveyi LuxR homologues, the well-conserved master transcriptional regulators for QS in Vibrio species. Crystallographic and biochemical analyses showed that QStatin binds tightly to a putative ligand-binding pocket in SmcR, the LuxR homologue in V. vulnificus, and changes the flexibility of the protein, thereby altering its transcription regulatory activity. Transcriptome analysis revealed that QStatin results in SmcR dysfunction, affecting the expression of SmcR regulon required for virulence, motility/chemotaxis, and biofilm dynamics. Notably, QStatin attenuated representative QS-regulated phenotypes in various Vibrio species, including virulence against the brine shrimp (Artemia franciscana). Together, these results provide molecular insights into the mechanism of action of an effective, sustainable QS inhibitor that is less susceptible to resistance than other antimicrobial agents and useful in controlling the virulence of Vibrio species in aquacultures.IMPORTANCE Yields of aquaculture, such as penaeid shrimp hatcheries, are greatly affected by vibriosis, a disease caused by pathogenic Vibrio infections. Since bacterial cell-to-cell communication, known as quorum sensing (QS), regulates pathogenesis of Vibrio species in marine environments, QS inhibitors have attracted attention as alternatives to conventional antibiotics in aquatic settings. Here, we used target-based high-throughput screening to identify QStatin, a potent and selective inhibitor of V. harveyi LuxR homologues, which are well-conserved master QS regulators in Vibrio species. Structural and biochemical analyses revealed that QStatin binds tightly to a putative ligand-binding pocket on SmcR, the LuxR homologue in V. vulnificus, and affects expression of QS-regulated genes. Remarkably, QStatin attenuated diverse QS-regulated phenotypes in various Vibrio species, including pathogenesis against brine shrimp, with no impact on bacterial viability. Taken together, the results suggest that QStatin may be a sustainable antivibriosis agent useful in aquacultures.

更新日期：2018-03-06

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