Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR.
Structure-Function Analyses of the N-Butanoyl l-Homoserine Lactone Quorum-Sensing Signal Define Features Critical to Activity in RhlR.
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DOI：
10.1021/acschembio.8b00577
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发表时间：
2018-09-21
影响因子：
4
通讯作者：
Blackwell HE
中科院分区：
文献类型：
--
作者：
Boursier ME;Moore JD;Heitman KM;Shepardson-Fungairino SP;Combs JB;Koenig LC;Shin D;Brown EC;Nagarajan R;Blackwell HE
铜绿假单胞菌是一种机会致病菌，在高种群密度下通过群体感应（QS）协调多种毒力表型的产生。LuxR型受体RhlR在铜绿假单胞菌QS过程中起重要作用，并且对开发调节该蛋白质活性的化学方法有相当大的兴趣。RhlR被简单的低分子量N-酰基-L-高丝氨酸内酯信号N-丁酰基-L-高丝氨酸内酯（BHL）激活。尽管RhlR在QS途径中的突出性正在显现，但对BHL支架的化学特征的探索有限，这些化学特征对其功能至关重要。在目前的研究中，我们试图系统地描绘结构-活性关系（SAR）驱动BHL活动的第一次。设计、合成BHL类似物的聚焦文库，并在基于细胞的报告基因测定中评估RhIR激动和拮抗作用。这些调查使我们能够定义一系列的BHL型配体的SAR和确定的RhlR受体的激活和抑制的关键结构基序。值得注意的是，我们鉴定了相对于BHL在RhlR中具有约10倍更高效力的激动剂，其对RhlR激动的选择性高于LasR，并且在铜绿假单胞菌背景中具有活性。本文报道的这些化合物和SAR应该为研究铜绿假单胞菌中RhlR的新化学策略铺平道路。
Pseudomonas aeruginosa is an opportunistic pathogen that coordinates the production of many virulence phenotypes at high population density via quorum sensing (QS). The LuxR-type receptor RhlR plays an important role in the P. aeruginosa QS process, and there is considerable interest in the development of chemical approaches to modulate the activity of this protein. RhlR is activated by a simple, low molecular weight N-acyl L-homoserine lactone signal, N-butanoyl-L-homoserine lactone (BHL). Despite the emerging prominence of RhlR in QS pathways, there has been limited exploration of the chemical features of the BHL scaffold that are critical to its function. In the current study, we sought to systematically delineate the structure-activity relationships (SARs) driving BHL activity for the first time. A focused library of BHL analogs was designed, synthesized, and evaluated in cell-based reporter gene assays for RhlR agonism and antagonism. These investigations allowed us to define a series of SARs for BHL-type ligands and identify structural motifs critical for both activation and inhibition of the RhlR receptor. Notably, we identified agonists that have ~10-fold higher potencies in RhlR relative to BHL, are highly selective for RhlR agonism over LasR, and are active in the P. aeruginosa background. These compounds and the SARs reported herein should pave a route toward new chemical strategies to study RhlR in P. aeruginosa.
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影响因子：
3.2
作者：
Glansdorp, FG;Thomas, GL;Spring, DR
通讯作者：
Spring, DR
影响因子：
3.2
作者：
Pearson, JP;Pesci, EC;Iglewski, BH
通讯作者：
Iglewski, BH
影响因子：
1.6
作者：
Ikeda, T;Kajiyama, K;Ohtake, H
通讯作者：
Ohtake, H
DOI：
10.1073/pnas.1114125108
发表时间：
2011-10-04
影响因子：
11.1
作者：
Lindemann, Andrea;Pessi, Gabriella;Harwood, Caroline S.
通讯作者：
Harwood, Caroline S.
影响因子：
3.7
作者：
Bjarnsholt T;Jensen PØ;Jakobsen TH;Phipps R;Nielsen AK;Rybtke MT;Tolker-Nielsen T;Givskov M;Høiby N;Ciofu O;Scandinavian Cystic Fibrosis Study Consortium
通讯作者：
Scandinavian Cystic Fibrosis Study Consortium