title: Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa.
abstract: 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.
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
  Box 422, New York, New York 10065, United States
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
  Box 422, New York, New York 10065, United States
authors.forename: Indrajeet
authors.initials: I
authors.lastname: Sharma
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
  Box 422, New York, New York 10065, United States
authors.forename: Debarshi
authors.initials: D
authors.lastname: Pratihar
authors.affiliation: Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University , 600 Moye Boulevard, Greenville, North Carolina 27834, United States.
authors.forename: L Lynn
authors.initials: LL
authors.lastname: Hudson
authors.affiliation: Department of Surgery, Harvard Medical School and Massachusettts General Hospital , 50 Blossom Street, Boston, Massachusetts 02114, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Maura
authors.forename: Tezcan
authors.initials: T
authors.lastname: Guney
authors.affiliation: Department of Surgery, Harvard Medical School and Massachusettts General Hospital , 50 Blossom Street, Boston, Massachusetts 02114, United States.|Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, United States.
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
authors.affiliation: Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University , 600 Moye Boulevard, Greenville, North Carolina 27834, United States.
authors.forename: Everett C
authors.initials: EC
authors.lastname: Pesci
authors.affiliation: Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University , 600 Moye Boulevard, Greenville, North Carolina 27834, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Coleman
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
  Box 422, New York, New York 10065, United States|Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue,
  Box 422, New York, New York 10065, United States
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
mesh_terms: D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015363:Quinolones / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D054852:Small Molecule Libraries; D003066:Coenzyme A Ligases