Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa.
Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa.
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DOI：
10.1021/acschembio.6b00575
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发表时间：
2016-11-18
影响因子：
4
通讯作者：
Tan, Derek S.
中科院分区：
文献类型：
--
作者：
Ji, Cheng;Sharma, Indrajeet;Pratihar, Debarshi;Hudson, L. Lynn;Maura, Damien;Guney, Tezcan;Rahme, Laurence G.;Pesci, Everett C.;Coleman, James P.;Tan, Derek S.
革兰氏阴性细菌病原体铜绿假单胞菌（Pseudomonasaeruginosa）使用由转录因子LasR、RhlR和MvfR（PqsR）调节的三个相互关联的细胞间信号传导系统，其通过小分子天然产物介导细菌细胞-细胞通信并控制多种毒力因子的产生。MvfR系统由喹诺酮类群体感应因子HHQ和PQS激活并控制其生物合成。这些喹诺酮类药物生物合成的关键步骤是由邻氨基苯甲酰基辅酶A合成酶PqsA催化的。为了开发PqsA抑制剂作为新的潜在的抗毒力抗生素，我们在此报告的设计和合成的磺酰腺嘌呤为基础的模拟物的邻氨基苯甲酰基-AMP反应中间体，是紧密结合的PqsA。生物化学、微生物学和药理学研究确定了两种有效的PqsA抑制剂，邻氨基苯甲酰基-AMS（1）和邻氨基苯甲酰基-AMSN（2），可降低铜绿假单胞菌菌株PA 14中的HHQ和PQS产量。然而，这些化合物不抑制毒力因子绿脓菌素的产生。此外，它们在化合物蓄积研究中表现出有限的细菌渗透。这项工作提供了迄今为止报道的最有效的PqsA抑制剂，并为未来开发具有改善细胞活性的类似物的努力奠定了基础，以进一步研究铜绿假单胞菌中喹诺酮生物合成和毒力因子产生之间的复杂关系以及靶向PqsA的治疗潜力。
The Gram-negative bacterial pathogen Pseudomonas aeruginosa uses three interconnected intercellular signaling systems regulated by the transcription factors LasR, RhlR, and MvfR (PqsR), which mediate bacterial cell–cell communication via small-molecule natural products and control the production of a variety of virulence factors. The MvfR system is activated by and controls the biosynthesis of the quinolone quorum sensing factors HHQ and PQS. A key step in the biosynthesis of these quinolones is catalyzed by the anthranilyl-CoA synthetase PqsA. To develop inhibitors of PqsA as novel potential antivirulence antibiotics, we report herein the design and synthesis of sulfonyladeonsine-based mimics of the anthranilyl-AMP reaction intermediate that is bound tightly by PqsA. Biochemical, microbiological, and pharmacological studies identified two potent PqsA inhibitors, anthranilyl-AMS (1) and anthranilyl-AMSN (2), that decreased HHQ and PQS production in P. aeruginosa strain PA14. However, these compounds did not inhibit production of the virulence factor pyocyanin. Moreover, they exhibited limited bacterial penetration in compound accumulation studies. This work provides the most potent PqsA inhibitors reported to date and sets the stage for future efforts to develop analogues with improved cellular activity to investigate further the complex relationships between quinolone biosynthesis and virulence factor production in P. aeruginosa and the therapeutic potential of targeting PqsA.
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影响因子：
14.8
作者：
Arora, Pooja;Goyal, Aneesh;Natarajan, Vivek T.;Rajakumara, Eerappa;Verma, Priyanka;Gupta, Radhika;Yousuf, Malikmohamed;Trivedi, Omita A.;Mohanty, Debasisa;Tyagi, Anil;Sankaranarayanan, Rajan;Gokhale, Rajesh S.
通讯作者：
Gokhale, Rajesh S.
影响因子：
--
作者：
Dulcey CE;Dekimpe V;Fauvelle DA;Milot S;Groleau MC;Doucet N;Rahme LG;Lépine F;Déziel E
通讯作者：
Déziel E
影响因子：
4
作者：
Davis, Tony D.;Gerry, Christopher J.;Tan, Derek S.
通讯作者：
Tan, Derek S.
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：
6.7
作者：
Kesarwani, Meenu;Hazan, Ronen;Rahme, Laurence G.
通讯作者：
Rahme, Laurence G.