Disruption of Quorum Sensing and Virulence in Burkholderia cenocepacia by a Structural Analogue of the cis-2-Dodecenoic Acid Signal
Disruption of Quorum Sensing and Virulence in Burkholderia cenocepacia by a Structural Analogue of the cis-2-Dodecenoic Acid Signal
复制标题
顺式-2-十二碳烯酸信号的结构类似物破坏新洋葱伯克霍尔德菌的群体感应和毒力
DOI：
10.1128/aem.00105-19
复制
发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Deng, Yinyue
中科院分区：
文献类型：
--
作者：
Cui, Chaoyu;Song, Shihao;Deng, Yinyue
新洋葱伯克霍尔德菌是一种重要的机会致病菌，可在易感个体中引起危及生命的感染，特别是在囊性纤维化和免疫功能低下的患者中。毒力的调节主要通过两种群体感应系统，即顺式-2-十二碳烯酸（BDSF）系统和N-酰基高丝氨酸内酯（阿勒）系统来实现。在本研究中，我们设计并鉴定了一种能够干扰B的不饱和脂肪酸化合物（顺式-14-甲基十五碳-2-烯酸[14-Me-C16：Δ2]）。cenocepacia QS信号传导和毒力。我们证明14-Me-C16：Δ2减少了B中BDSF和阿勒信号的产生。cenocepacia。它还损害了各种伯克霍尔德氏菌属物种的QS调节表型。这些结果表明，14-Me-C16：Δ2可以干扰许多伯克霍尔德氏菌的QS信号，并可能被开发为一种新的抗菌剂。摘要群体感应（QS）信号被细菌病原体广泛用于响应细胞群体密度的变化来控制生物学功能和毒力。新洋葱伯克霍尔德氏菌采用顺式-2-十二碳烯酸（称为伯克霍尔德氏菌扩散信号因子[BDSF]）QS系统通过调节细胞内环二磷酸鸟苷（c-di-GMP）水平来调节N-酰基高丝氨酸内酯（阿勒）信号产生和毒力的分子机制。因此，BDSF信号传导的抑制可以提供针对BDSF调节的细菌感染的基于非抗生素的治疗策略。在这项研究中，我们报告的BDSF信号的小分子模拟物的合成，并评估其抑制BDSF QS信号在B的能力。cenocepacia。在B中，观察到BDSF的新结构类似物14-Me-C16：Δ2（顺-14-甲基十五碳-2-烯酸）抑制BDSF产生并损害BDSF调节的表型。包括运动性、生物膜形成和毒力，而它不抑制该病原体的生长速率。14-Me-C16：Δ2也减少了阿勒信号的产生。遗传和生化分析表明，14-Me-C16：Δ2通过降低BDSF和AHL信号的表达，抑制了BDSF和AHL信号的产生。值得注意的是，14-Me-C16：Δ2减弱了各种伯克霍尔德氏菌属物种中的BDSF调节表型。这些发现表明，14-Me-C16：Δ2可能通过干扰其QS信号传导而被开发为针对致病性伯克霍尔德氏菌物种的新治疗剂。重要性新洋葱伯克霍尔德菌是一种重要的机会致病菌，可在易感个体中引起危及生命的感染，特别是在囊性纤维化和免疫功能低下的患者中。毒力的调节主要通过两种群体感应系统，即顺式-2-十二碳烯酸（BDSF）系统和N-酰基高丝氨酸内酯（阿勒）系统来实现。在本研究中，我们设计并鉴定了一种能够干扰B的不饱和脂肪酸化合物（顺式-14-甲基十五碳-2-烯酸[14-Me-C16：Δ2]）。cenocepacia QS信号传导和毒力。我们证明14-Me-C16：Δ2减少了B中BDSF和阿勒信号的产生。cenocepacia。它还损害了各种伯克霍尔德氏菌属物种的QS调节表型。这些结果表明，14-Me-C16：Δ2可以干扰许多伯克霍尔德氏菌的QS信号，并可能被开发为一种新的抗菌剂。
Burkholderia cenocepacia is an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two types of quorum sensing (QS) systems, including the cis-2-dodecenoic acid (BDSF) system and N-acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (cis-14-methylpentadec-2-enoic acid [14-Me-C16:Δ2]) that is capable of interfering with B. cenocepacia QS signaling and virulence. We demonstrate that 14-Me-C16:Δ2 reduced BDSF and AHL signal production in B. cenocepacia. It also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that 14-Me-C16:Δ2 could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent. ABSTRACT Quorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities. Burkholderia cenocepacia employs a molecular mechanism in which the cis-2-dodecenoic acid (named Burkholderia diffusible signal factor [BDSF]) QS system regulates N-acyl homoserine lactone (AHL) signal production and virulence by modulating intracellular levels of cyclic diguanosine monophosphate (c-di-GMP). Thus, inhibition of BDSF signaling may offer a non-antibiotic-based therapeutic strategy against BDSF-regulated bacterial infections. In this study, we report the synthesis of small-molecule mimics of the BDSF signal and evaluate their ability to inhibit BDSF QS signaling in B. cenocepacia. A novel structural analogue of BDSF, 14-Me-C16:Δ2 (cis-14-methylpentadec-2-enoic acid), was observed to inhibit BDSF production and impair BDSF-regulated phenotypes in B. cenocepacia, including motility, biofilm formation, and virulence, while it did not inhibit the growth rate of this pathogen. 14-Me-C16:Δ2 also reduced AHL signal production. Genetic and biochemical analyses showed that 14-Me-C16:Δ2 inhibited the production of the BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Notably, 14-Me-C16:Δ2 attenuated BDSF-regulated phenotypes in various Burkholderia species. These findings suggest that 14-Me-C16:Δ2 could potentially be developed as a new therapeutic agent against pathogenic Burkholderia species by interfering with their QS signaling. IMPORTANCE Burkholderia cenocepacia is an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two types of quorum sensing (QS) systems, including the cis-2-dodecenoic acid (BDSF) system and N-acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (cis-14-methylpentadec-2-enoic acid [14-Me-C16:Δ2]) that is capable of interfering with B. cenocepacia QS signaling and virulence. We demonstrate that 14-Me-C16:Δ2 reduced BDSF and AHL signal production in B. cenocepacia. It also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that 14-Me-C16:Δ2 could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent.