title: Fine-Tuning Covalent Inhibition of Bacterial Quorum Sensing.
abstract: Emerging antibiotic resistance among human pathogens has galvanized efforts to find alternative routes to combat bacterial virulence. One new approach entails interfering with the ability of bacteria to coordinate population-wide gene expression, or quorum sensing (QS), thus inhibiting the production of virulence factors and biofilm formation. We have recently developed such a strategy by targeting LasR, the master regulator of QS in the opportunistic human pathogen Pseudomonas aeruginosa, through the rational design of covalent inhibitors closely based on the core structure of the native ligand. We now report several groups of new inhibitors, one of which, fluoro-substituted ITC-12, displayed complete covalent modification of LasR, as well as effective QS inhibition in vitro and promising in vivo results. In addition to their potential clinical relevance, this series of synthetic QS modulators can be used as a tool to further unravel the complicated QS regulation in P. aeruginosa.
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors: Neri
authors: N
authors: Amara
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors: Rachel
authors: R
authors: Gregor
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors: Josep
authors: J
authors: Rayo
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors: Rambabu
authors: R
authors: Dandela
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
authors: Erik
authors: E
authors: Daniel
authors: Department of Life Sciences and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beersheva, Israel.
authors: Nina
authors: N
authors: Liubin
authors: Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam, Free University Amsterdam and the University of Amsterdam, Amsterdam, The Netherlands.
authors: H Marjo E
authors: HM
authors: Willems
authors: Department of Life Sciences and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beersheva, Israel.
authors: Anat
authors: A
authors: Ben-Zvi
authors: Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam, Free University Amsterdam and the University of Amsterdam, Amsterdam, The Netherlands.
authors: Bastiaan P
authors: BP
authors: Krom
authors: Department of Chemistry and, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er Sheva, Israel. meijler@bgu.ac.il.
authors: Michael M
authors: MM
authors: Meijler
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D018441:Biofilms / Q000187:drug effects; D020134:Catalytic Domain; D002942:Circular Dichroism; D017879:Isothiocyanates / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D053038:Quorum Sensing / Q000187:drug effects*; D015534:Trans-Activators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017879:Isothiocyanates; C080365:LasR protein, Pseudomonas aeruginosa; D015534:Trans-Activators; D037521:Virulence Factors; C088386:homoserine lactone; C037152:isothiocyanic acid; D015107:4-Butyrolactone
keywords: bacterial infection; covalent inhibitors; isothiocyanates; quorum sensing; virulence