MexEF-OprN Efflux Pump Exports the <em>Pseudomonas</em> Quinolone Signal (PQS) Precursor HHQ (4-hydroxy-2-heptylquinoline)

Bacterial cells have evolved the capacity to communicate between each other via small diffusible chemical signals termed autoinducers. Pseudomonas aeruginosa is an opportunistic pathogen involved, among others, in cystic fibrosis complications. Virulence of P. aeruginosa relies on its ability to produce a number of autoinducers, including 4-hydroxy-2-alkylquinolines (HAQ). In a cell density-dependent manner, accumulated signals induce the expression of multiple targets, especially virulence factors. This phenomenon, called quorum sensing, promotes bacterial capacity to cause disease. Furthermore, P. aeruginosa possesses many multidrug efflux pumps conferring adaptive resistance to antibiotics. Activity of some of these efflux pumps also influences quorum sensing. The present study demonstrates that the MexEF-OprN efflux pump modulates quorum sensing through secretion of a signalling molecule belonging to the HAQ family. Moreover, activation of MexEF-OprN reduces virulence factor expression and swarming motility. Since MexEF-OprN can be activated in infected hosts even in the absence of antibiotic selective pressure, it could promote establishment of chronic infections in the lungs of people suffering from cystic fibrosis, thus diminishing the immune response to virulence factors. Therapeutic drugs that affect multidrug efflux pumps and HAQ-mediated quorum sensing would be valuable tools to shut down bacterial virulence.细菌细胞已演化出通过小型可扩散化学信号进行相互通讯的能力，这类信号被称为自体诱导物（autoinducer）。铜绿假单胞菌（Pseudomonas aeruginosa）是一种机会致病菌，可引发包括囊性纤维化并发症在内的多种感染。该菌的毒力依赖于其产生多种自体诱导物的能力，其中包括4-羟基-2-烷基喹啉（4-hydroxy-2-alkylquinolines，HAQ）。当信号分子积累至一定浓度后，会以细胞密度依赖的方式诱导多种靶标基因的表达，尤其是毒力因子。这一现象被称为群体感应（quorum sensing），可增强细菌的致病能力。此外，铜绿假单胞菌拥有多种多药外排泵，可赋予其对抗生素的适应性耐药性。其中部分外排泵的活性还会对群体感应产生调控作用。本研究证实，MexEF-OprN外排泵可通过分泌一类属于HAQ家族的信号分子，对群体感应进行调控。不仅如此，MexEF-OprN的激活还会降低毒力因子的表达水平与群集运动能力。由于即使在无抗生素选择压力的情况下，MexEF-OprN也可在感染宿主中被激活，因此它可能会促进囊性纤维化患者肺部慢性感染的建立，进而削弱机体针对毒力因子的免疫应答。能够靶向调控多药外排泵及HAQ介导的群体感应的治疗性药物，将成为抑制细菌毒力的有效工具。