Disarming the virulence arsenal of Pseudomonas aeruginosa by blocking two-component system signaling
Disarming the virulence arsenal of Pseudomonas aeruginosa by blocking two-component system signaling
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DOI：
10.1039/c8sc02496k
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发表时间：
2018-10-07
期刊：
影响因子：
8.4
通讯作者：
Carlson, Erin E.
中科院分区：
文献类型：
--
作者：
Goswami, Manibarsha;Espinasse, Adeline;Carlson, Erin E.
铜绿假单胞菌感染已达到严重威胁状态，需要新的治疗方法。抑制与其致病性密切相关的关键信号酶组氨酸激酶（HK）已被认为是一种有效的治疗新策略。在本文中，我们证明了这种方法与基于苯并噻唑的HK抑制剂的潜力，该抑制剂干扰烧伤创面铜绿假单胞菌分离株PA14中的多个毒力途径。具体来说，我们的化合物显著降低了这种生物体产生的毒性代谢物的水平，这些代谢物参与群体感应和氧化还原平衡机制。它们还可能通过影响其运动性附属物来降低这种生物体聚集和附着在表面上的能力。定量转录分析的大肠杆菌处理的培养物显示大量的扰动，以多种途径，包括反应调节剂GacA的表达，同源的合作伙伴的超级调节器的毒力，香港GacS，以及鞭毛和皮利形成。这些有希望的结果证实，阻断铜绿假单胞菌中的细菌信号传导对毒力行为具有显著影响，特别是在表面相关感染的情况下。
Pseudomonas aeruginosa infections have reached a critical threat status making novel therapeutic approaches required. Inhibiting key signaling enzymes known as the histidine kinases (HKs), which are heavily involved with its pathogenicity, has been postulated to be an effective new strategy for treatment. Herein, we demonstrate the potential of this approach with benzothiazole-based HK inhibitors that perturb multiple virulence pathways in the burn wound P. aeruginosa isolate, PA14. Specifically, our compounds significantly reduce the level of toxic metabolites generated by this organism that are involved in quorum-sensing and redox-balancing mechanisms. They also decrease the ability of this organism to swarm and attach to surfaces, likely by influencing their motility appendages. Quantitative transcription analysis of inhibitor-treated cultures showed substantial perturbations to multiple pathways including expression of response regulator GacA, the cognate partner of the super regulator of virulence, HK GacS, as well as flagella and pili formation. These promising results establish that blocking of bacterial signaling in P. aeruginosa has dramatic consequences on virulence behaviours, especially in the context of surface-associated infections.