Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR.
Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR.
复制标题
DOI：
10.1016/j.ejmech.2020.112778
复制
发表时间：
2020-12-15
影响因子：
6.7
通讯作者：
Stocks MJ
中科院分区：
文献类型：
--
作者：
Grossman S;Soukarieh F;Richardson W;Liu R;Mashabi A;Emsley J;Williams P;Cámara M;Stocks MJ
近年来，耐多药和广泛耐药铜绿假单胞菌病例数量不断增加，迫切需要新的治疗方法来治愈可能致命的感染。其中一种方法是毒力衰减，即使用旨在降低致病性而不提供杀菌作用的抗毒力化合物来治疗感染。P. aeruginosa使用pqs群体感应（QS）系统来协调大量毒力决定因子的表达以及细菌与宿主的相互作用，因此是一个很好的抗毒靶点。我们合成并鉴定了一系列新的含有噻唑的喹唑啉酮类化合物，这些化合物能够抑制pqs - QS系统的转录调控因子PqsR。利用mCTX: ppqsa - luxs为基础的生物报告基因，对铜绿假单胞菌PAO1-L和PA14菌株进行了全细胞检测，结果显示化合物具有较高的效价（IC50 < 300 nM）。结构评价通过x射线晶体学确定了四种类似物在PqsR配体结合域中的结合模式。进一步的研究表明，6-氯-3（（2-戊基噻唑-4-酰基）甲基）喹唑啉-4(3H)- 1（18）和6-氯-3（（2-己基噻唑-4-酰基）甲基）喹唑啉-4(3H)- 1（19）能够减弱pqsr调控的毒力因子pyocyanin的产生。化合物18和19在A549人上皮肺细胞系中显示出较低的细胞毒性，这使它们适合进一步的临床前评估。铜绿假单胞菌-一种革兰氏阴性致病菌。群体感应-一种细胞间的通讯策略，由微生物用来协调各种毒力因子的产生。抑制铜绿假单胞菌喹诺酮类信号受体信号的PqsR小分子抑制剂。x射线晶体结构——用于证明配体在蛋白质结构中的三维结构取向。
Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation. Pseudomonas aeruginosa – a Gram-negative pathogenic bacterium. Quorum sensing – a cell-to-cell communication strategy used by microbes to coordinate the production of various virulence factors. Inhibitors of PqsR – small molecules that inhibit the signal of Pseudomonas aeruginosa Quinolone Signal Receptor. X-ray crystal structure – used to demonstrate the 3-D structural orientation of the ligand in the protein structure.
登录
查看更多内容
影响因子：
2.9
作者：
Albuquerque P;Casadevall A
通讯作者：
Casadevall A
影响因子：
6.7
作者：
Ilangovan A;Fletcher M;Rampioni G;Pustelny C;Rumbaugh K;Heeb S;Cámara M;Truman A;Chhabra SR;Emsley J;Williams P
通讯作者：
Williams P
影响因子：
11.3
作者：
Heeb S;Fletcher MP;Chhabra SR;Diggle SP;Williams P;Cámara M
通讯作者：
Cámara M
影响因子：
3.6
作者：
Diggle, SP;Winzer, K;Williams, P
通讯作者：
Williams, P
影响因子：
15.9
作者：
BRITIGAN, BE;ROEDER, TL;COX, CD
通讯作者：
COX, CD