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Identification of FDA-approved antivirulence drugs targeting the Pseudomonas aeruginosa quorum sensing effector protein PqsE.
Virulence ( IF 5.2 ) Pub Date : 2020-05-28 , DOI: 10.1080/21505594.2020.1770508
Valerio Baldelli 1 , Francesca D'Angelo 1 , Viola Pavoncello 1 , Ersilia Vita Fiscarelli 2 , Paolo Visca 1 , Giordano Rampioni 1 , Livia Leoni 1
Affiliation  

The ability of the bacterial pathogen Pseudomonas aeruginosa to cause both chronic and acute infections mainly relies on its capacity to finely modulate the expression of virulence factors through a complex network of regulatory circuits, including the pqs quorum sensing (QS) system. While in most QS systems the signal molecule/receptor complexes act as global regulators that modulate the expression QS-controlled genes, the main effector protein of the pqs system is PqsE. This protein is involved in the synthesis of the QS signal molecules 2-alkyl-4(1H)-quinolones (AQs), but it also modulates the expression of genes involved in virulence factors production and biofilm formation via AQ-independent pathway(s). P. aeruginosa pqsE mutants disclose attenuated virulence in plant and animal infection models, hence PqsE is considered a good target for the development of antivirulence drugs against P. aeruginosa.In this study, the negative regulation exerted by PqsE on its own transcription has been exploited to develop a screening system for the identification of PqsE inhibitors in a library of FDA-approved drugs. This led to the identification of nitrofurazone and erythromycin estolate, two antibiotic compounds that reduce the expression of PqsE-dependent virulence traits and biofilm formation in the model strain P. aeruginosa PAO1 at concentrations far below those affecting the bacterial growth rate. Notably, both drugs reduce the production of the PqsE-controlled virulence factor pyocyanin also in P. aeruginosa strains isolated from cystic fibrosis patients, and do not antagonize the activity of antibiotics commonly used to treat P. aeruginosa infection.

中文翻译:

针对铜绿假单胞菌群体感应效应蛋白PqsE的FDA批准的抗毒药物的鉴定。

细菌病原体铜绿假单胞菌引起慢性和急性感染的能力主要取决于其通过复杂的调节电路网络(包括pqs群体感应(QS)系统)精确调节毒力因子表达的能力。虽然在大多数QS系统中,信号分子/受体复合物充当调节QS受控基因表达的全局调节剂,但pqs系统的主要效应蛋白是PqsE。该蛋白质参与QS信号分子2-烷基-4(1H)-喹诺酮(AQs)的合成,但它也通过非AQ途径调节与致病因子产生和生物膜形成有关的基因的表达。 。铜绿假单胞菌pqsE突变体揭示了动植物感染模型中毒力减弱的情况,因此,PqsE被认为是开发针对铜绿假单胞菌的抗毒药物的良好靶标。在这项研究中,利用PqsE对自身转录产生的负调节作用来开发筛选系统,用于鉴定PqsE抑制剂。 FDA批准的药物。这就导致了对呋喃酮和依托红霉素的鉴定,这两种抗生素化合物可降低模型菌株铜绿假单胞菌PAO1中PqsE依赖性毒力特性的表达和生物膜形成,其浓度远低于影响细菌生长速率的浓度。值得注意的是,两种药物均会降低从囊性纤维化患者中分离出的铜绿假单胞菌菌株中PqsE控制的毒力因子绿脓素的产生,并且不会拮抗通常用于治疗P的抗生素的活性。
更新日期:2020-05-28
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