Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication.

@article{citeulike:2891513, abstract = {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.}, address = {Department of Surgery, Harvard Medical School and Shriners Burns Institute, Massachusetts General Hospital, Boston, MA 02114, USA.}, author = {D\'{e}ziel, E. and L\'{e}pine, F. and Milot, S. and He, J. and Mindrinos, M. N. and Tompkins, R. G. and Rahme, L. G. }, citeulike-article-id = {2891513}, doi = {10.1073/pnas.0307694100}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {aa, aeruginosa, haq, p, qs, regulation}, month = {February}, number = {5}, pages = {1339--1344}, posted-at = {2008-06-13 15:09:53}, priority = {2}, title = {Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication.}, url = {http://dx.doi.org/10.1073/pnas.0307694100}, volume = {101}, year = {2004} }

TY - JOUR ID - citeulike:2891513 L3 - citeulike-article-id:2891513 TI - Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication. JF - Proceedings of the National Academy of Sciences of the United States of America VL - 101 IS - 5 SP - 1339 EP - 1344 AD - Department of Surgery, Harvard Medical School and Shriners Burns Institute, Massachusetts General Hospital, Boston, MA 02114, USA. SN - 0027-8424 N2 - 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. KW - aa KW - aeruginosa KW - haq KW - p KW - qs KW - regulation AU - Déziel, E AU - Lépine, F AU - Milot, S AU - He, J AU - Mindrinos, MN AU - Tompkins, RG AU - Rahme, LG PY - 2004/02/03/ UR - http://dx.doi.org/10.1073/pnas.0307694100 ER -