title: Triazole-containing N-acyl homoserine lactones targeting the quorum sensing system in Pseudomonas aeruginosa.
abstract: In an attempt to devise new antimicrobial treatments for biofilm infections, the bacterial cell-cell communication system termed quorum sensing has emerged as an attractive target. It has proven possible to intercept the communication system by synthetic non-native ligands and thereby lower the pathogenesis and antibiotic tolerance of a bacterial biofilm. To identify the structural elements important for antagonistic or agonistic activity against the Pseudomonas aeruginosa LasR protein, we report the synthesis and screening of new triazole-containing mimics of natural N-acyl homoserine lactones. A series of azide- and alkyne-containing homoserine lactone building blocks was used to prepare an expanded set of 123 homoserine lactone analogues through a combination of solution- and solid-phase synthesis methods. The resulting compounds were subjected to cell-based quorum sensing screening assays, thereby revealing several bioactive compounds, including 13 compounds with antagonistic activity and 9 compounds with agonistic activity.
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Mette R
authors.initials: MR
authors.lastname: Hansen
authors.affiliation: Costerton Biofilm Center, Department of International Health, Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Jakobsen
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Claus G
authors.initials: CG
authors.lastname: Bang
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Anders Emil
authors.initials: AE
authors.lastname: Cohrt
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Casper L
authors.initials: CL
authors.lastname: Hansen
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Janie W
authors.initials: JW
authors.lastname: Clausen
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Le Quement
authors.affiliation: Costerton Biofilm Center, Department of International Health, Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Tim
authors.initials: T
authors.lastname: Tolker-Nielsen
authors.affiliation: Costerton Biofilm Center, Department of International Health, Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark; Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.affiliation: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark; Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore. Electronic address: ten@kemi.dtu.dk.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
mesh_terms: D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D053038:Quorum Sensing / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D014230:Triazoles; C088386:homoserine lactone; D015107:4-Butyrolactone
keywords: 1,2,3-Triazole; Antibiotics; Homoserine lactone; Pseudomonas aeruginosa; Quorum sensing