title: Identification of LasR ligands through a virtual screening approach.
abstract: With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity.
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Skovstrup
authors.forename: Sebastian Thordal
authors.initials: ST
authors.lastname: Le Quement
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.forename: Tim Holm
authors.initials: TH
authors.lastname: Jakobsen
authors.forename: Morten
authors.initials: M
authors.lastname: Harmsen
authors.forename: Tim
authors.initials: T
authors.lastname: Tolker-Nielsen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nielsen
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.forename: Olivier
authors.initials: O
authors.lastname: Taboureau
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D053038:Quorum Sensing / Q000187:drug effects*; D015534:Trans-Activators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D008024:Ligands; D015534:Trans-Activators