Abstract：
Burkholderia cenocepacia is a human opportunistic pathogen that mostly employs two types of quorum-sensing (QS) systems to regulate its various biological functions and pathogenicity: the cis-2-dodecenoic acid (BDSF) system and the N-acyl homoserine lactone (AHL) system. In this study, we reported that oridonin, which was screened from a collection of natural products, disrupted important B. cenocepacia phenotypes, including motility, biofilm formation, protease production, and virulence. Genetic and biochemical analyses showed that oridonin inhibited the production of BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Furthermore, we revealed that oridonin directly binds to the regulator RqpR of the two-component system RqpSR that dominates the above-mentioned QS systems to inhibit the expression of the BDSF and AHL signal synthase-encoding genes. Oridonin also binds to the transcriptional regulator CepR of the cep AHL system to inhibit its binding to the promoter of bclACB. These findings suggest that oridonin could potentially be developed as a new QS inhibitor against pathogenic B. cenocepacia. IMPORTANCE Burkholderia cenocepacia is an important human opportunistic pathogen that can cause life-threatening infections in susceptible individuals. It employs quorum-sensing (QS) systems to regulate biological functions and virulence. In this study, we have identified a lead compound, oridonin, that is capable of interfering with B. cenocepacia QS signaling and physiology. We demonstrate that oridonin suppressed cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) signal production and attenuated virulence in B. cenocepacia. Oridonin also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that oridonin could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent.
摘要：
伯克霍尔德氏菌是人类机会性病原体，主要采用两种类型的群体感应（QS）系统来调节其各种生物学功能和致病性：顺式-2-十二碳烯酸（BDSF）系统和N-酰基高丝氨酸内酯（AHL）系统。在这项研究中,我们报道了冬凌草甲素，从一系列天然产品中筛选出来，破坏了重要的隐孢子虫表型，包括运动性，生物膜的形成，蛋白酶生产，和毒力。遗传和生化分析表明，冬凌草甲素通过降低其合酶编码基因的表达来抑制BDSF和AHL信号的产生。此外，我们揭示了冬凌草甲素直接与主导上述QS系统的双组分系统RqpSR的调节因子RqpR结合，以抑制BDSF和AHL信号合酶编码基因的表达。冬凌草甲素还与cepAHL系统的转录调节因子CepR结合，以抑制其与bclACB启动子的结合。这些发现表明，冬凌草甲素可能被开发为一种新的QS抑制剂，以对抗致病性白头蛇。重要性伯克霍尔德氏菌是一种重要的人类机会性病原体，可在易感个体中引起危及生命的感染。它采用群体感应（QS）系统来调节生物功能和毒力。在这项研究中,我们已经确定了一种先导化合物，冬凌草甲素,它能够干扰隐孢子虫QS信号传导和生理学。我们证明了冬凌草甲素抑制了顺式-2-十二烯酸（BDSF）和N-酰基高丝氨酸内酯（AHL）信号的产生，并减轻了黑带芽孢杆菌的毒力。冬凌草素还损害了各种伯克霍尔德氏菌物种中QS调节的表型。这些结果表明，冬凌草甲素可以干扰许多伯克霍尔德菌物种的QS信号传导，并可能被开发为一种新的抗菌剂。
