Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication
Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication
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DOI：
10.1073/pnas.0307694100
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发表时间：
2004-02-03
影响因子：
11.1
通讯作者：
Rahme, LG
中科院分区：
文献类型：
--
作者：
Déziel, E;Lépine, F;Rahme, LG
细菌群落利用“群体感应”（QS）通过细胞外信号分子（如N-酰基-L-高丝氨酸内酯（AHL））的作用来协调其群体行为。多功能和普遍存在的条件致病菌铜绿假单胞菌是AHL介导的QS的一个研究充分的模型。该物种还产生不同于AHL的细胞间信号，即3，4-二羟基-2-庚基喹啉（PQS），其属于先前因其抗微生物活性而鉴定的特征性较差的4-羟基-2-烷基喹啉（HAQ）家族。在这里，我们使用液相色谱（LC）/MS，遗传学和全基因组表达来研究HAQs的结构，生物合成，调节和活性。我们表明，pqsA-E操纵子编码的酶，催化生物合成的五个不同类别的HAQs，并建立这些化合物的合成序列，其中包括有效的细胞色素抑制剂和抗生素活性对人类肠道和病原菌。我们发现邻氨基苯甲酸，PhnAB合酶的产物，是HAQs的主要前体，HAQ同源物4-羟基-2-庚基喹啉（HHQ）是PQS信号分子的直接前体。值得注意的是，尽管phnAB和pqsA-E受到毒性相关转录因子MvfR的正调控，而MvfR也是几个QS调节基因表达所需的，但HHQ向PQS的转化却受到LasR的控制。最后，我们的研究结果表明，HHQ本身既从细菌细胞释放，又被细菌细胞吸收，在那里它被转化为PQS，这表明它在细胞间通讯途径中起信使分子的作用。HAQ信号转导代表了铜绿假单胞菌介导的感染的药理学干预的潜在靶点。
Bacterial communities use "quorum sensing" (QS) to coordinate their population behavior through the action of extracellular signal molecules, such as the N-acyl-L-homoserine lactones (AHLs). The versatile and ubiquitous opportunistic pathogen Pseudomonas aeruginosa is a well-studied model for AHL-mediated QS. This species also produces an intercellular signal distinct from AHLs, 3,4-dihydroxy-2-heptylquinoline (PQS), which belongs to a family of poorly characterized 4-hydroxy-2-alkylquinolines (HAQs) previously identified for their antimicrobial activity. Here we use liquid chromatography (LC)/MS, genetics, and whole-genome expression to investigate the structure, biosynthesis, regulation, and activity of HAQs. We show that the pqsA-E operon encodes enzymes that catalyze the biosynthesis of five distinct classes of HAQs, and establish the sequence of synthesis of these compounds, which include potent cytochrome inhibitors and antibiotics active against human commensal and pathogenic bacteria. We find that anthranilic acid, the product of the PhnAB synthase, is the primary precursor of HAQs and that the HAQ congener 4-hydroxy-2-heptylquinoline (HHQ) is the direct precursor of the PQS signaling molecule. Significantly, whereas phnAB and pqsA-E are positively regulated by the virulence-associated transcription factor MvfR, which is also required for the expression of several QS-regulated genes, the conversion of HHQ to PQS is instead controlled by LasR. Finally, our results reveal that HHQ is itself both released from, and taken up by, bacterial cells where it is converted into PQS, suggesting that it functions as a messenger molecule in a cell-to-cell communication pathway. HAQ signaling represents a potential target for the pharmacological intervention of P. aeruginosa-mediated infections.