Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa
Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa
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DOI：
10.1128/aac.01296-18
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发表时间：
2018-11-01
影响因子：
4.9
通讯作者：
Rampioni, Giordano
中科院分区：
文献类型：
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作者：
D'Angelo, Francesca;Baldelli, Valerio;Rampioni, Giordano
长期使用抗生素导致了多重耐药细菌的出现。对抗细菌感染的一个有希望的策略是在不影响生长的情况下阻碍它们对宿主环境的适应性。在这种情况下，控制多种人类病原体毒力因子产生和生物膜形成的细胞间通讯系统群体感应（QS）被认为是一个理想的目标。在这里，我们描述了通过筛选1600种美国食品和药物管理局批准的药物库，鉴定出人类病原体铜绿假单胞菌pqs - QS系统的新抑制剂。基因工程菌株的表型分析和硅分子对接表明，抗真菌药物克霉唑和咪康唑以及一种抗革兰氏阳性病原体的抗菌化合物clofotol可能通过靶向转录调节因子PqsR抑制pqs系统。最具活性的抑制剂clofotol特异性抑制pqs控制的P. aeruginosa毒力性状的表达，如pyocyanin的产生、蜂群运动、生物膜的形成以及与铁载体产生有关的基因的表达。此外，clofotol对铜绿假单胞菌（P. aeruginosa）感染有保护作用，并抑制囊性纤维化患者铜绿假单胞菌分离株的pqs - QS系统。值得注意的是，clofotol已经被批准用于临床治疗由革兰氏阳性细菌病原体引起的肺部感染；因此，该药物作为铜绿假单胞菌肺部感染的抗毒剂具有相当大的临床潜力。
The long-term use of antibiotics has led to the emergence of multidrug-resistant bacteria. A promising strategy to combat bacterial infections aims at hampering their adaptability to the host environment without affecting growth. In this context, the intercellular communication system quorum sensing (QS), which controls virulence factor production and biofilm formation in diverse human pathogens, is considered an ideal target. Here, we describe the identification of new inhibitors of the pqs QS system of the human pathogen Pseudomonas aeruginosa by screening a library of 1,600 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the pqs system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of pqs-controlled virulence traits in P. aeruginosa, such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens; hence, this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections.