伯克霍尔德氏菌是一种与囊性纤维化(CF)患者特别相关的机会性呼吸道病原体。主要通过两个群体感应(QS)系统(CepI/R和CciI/R)调节其生物学功能和毒力因子。耐多药的伯克霍尔德氏菌的高度持续发病率对公共卫生构成了全球威胁。在这项研究中,我们调查了酪胺的作用,一种生物胺,关于伯克霍尔德氏菌的QS系统。遗传和生化分析表明,酪胺通过阻断CepI/R和CciI/R系统来抑制N-己酰基-高丝氨酸(AHL)信号分子(C8-HSL和C6-HSL)的产生。因此,QS系统的抑制导致各种毒力因子的产生减少,如生物膜的形成,胞外多糖,脂肪酶,和蜂拥而至的运动。值得注意的是,作为一种潜在的群体感应抑制剂,酪胺在Galleriamellonella幼虫体内表现出低毒性,并具有Lipinski的五条规则。根据SwissADME数据库和ProTox-II服务器,它还显示出较高的胃肠道吸收和穿越血脑屏障的能力。此外,发现酪胺可增强四环素在降低海绵状笼霉幼虫感染模型中的伯克霍尔德氏菌感染性方面的功效。因此,酪胺可能是与传统抗菌药物联合治疗的有希望的候选药物,以提高其对伯克霍尔德氏菌的疗效。
Burkholderia cenocepacia is an opportunistic respiratory pathogen of particular relevance to patients with cystic fibrosis (CF), primarily regulating its biological functions and virulence factors through two quorum sensing (QS) systems (CepI/R and CciI/R). The highly persistent incidence of multidrug resistant Burkholderia cenocepacia poses a global threat to public health. In this study, we investigated the effects of tyramine, one biogenic amine, on the QS systems of Burkholderia cenocepacia. Genetic and biochemical analyses revealed that tyramine inhibited the production of N-hexanoyl-homoserine (AHL) signaling molecules (C8-HSL and C6-HSL) by blocking the CepI/R and CciI/R systems. As a result, the inhibition of QS systems leads to reduced production of various virulence factors, such as biofilm formation, extracellular polysaccharides, lipase, and swarming motility. Notably, as a potential quorum sensing inhibitor, tyramine exhibits low toxicity in vivo in Galleria mellonella larvae and is well characterized by Lipinski\'s five rules. It also shows high gastrointestinal absorption and the ability to cross the blood-brain barrier according to SwissADME database and ProTox-II server. Additionally, tyramine was found to enhance the efficacy of tetracycline in reducing the infectivity of Burkholderia cenocepacia in Galleria mellonella larvae infection model. Therefore, tyramine could be a promising candidate for combination therapy with traditional antimicrobials to improve their effectiveness against Burkholderia cenocepacia.