Synthetic homoserine lactone-derived sulfonylureas as inhibitors of Vibrio fischeri quorum sensing regulator

INSA Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique, Bât J. Verne, 20 av A. Einstein, 69621 Villeurbanne Cedex, France.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 05/2008; 16(7):3550-6. DOI: 10.1016/j.bmc.2008.02.023
Source: PubMed


A series of 9 homoserine lactone-derived sulfonylureas substituted by an alkyl chain, some of them bearing a phenyl group at the extremity, have been prepared. All compounds were found to inhibit the action of 3-oxo-hexanoyl-L-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri, the aliphatic compounds being more active than their phenyl-substituted counterparts. Molecular modelling studies performed on the most active compound in each series suggest that the antagonist activity could be related to the perturbation of the hydrogen-bond network in the ligand-protein complexes.

Download full-text


Available from: Sylvie Reverchon
  • Source
    • "Changes in the amide function bridging the lactone ring and the fatty acid also influences the AHL binding activity to receptor proteins, since the amide forms hydrogen bonds with a conserved tyrosine and aspartic acid in the AHL binding pocket (Vannini et al., 2002; Zhang et al., 2002). Changing the amide to a sulfonamide and/or a urea has been predicted to result in the formation of an additional hydrogen bond between a tyrosine residue in the ligand pocket and the sulfonamide, and to strengthen the hydrogen bond between the aspartic acid and the external NH of urea (Castang et al., 2004; Frezza et al., 2006, 2008). Compounds with either or both modifications have showed antagonistic behaviors with the Vibrio fischeri LuxR receptor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bacteria use a cell-to-cell communication activity termed "quorum sensing" to coordinate group behaviors in a cell density dependent manner. Quorum sensing influences the expression profile of diverse genes, including antibiotic tolerance and virulence determinants, via specific chemical compounds called "autoinducers". During quorum sensing, Gram-negative bacteria typically use an acylated homoserine lactone (AHL) called autoinducer 1. Since the first discovery of quorum sensing in a marine bacterium, it has been recognized that more than 100 species possess this mechanism of cell-to-cell communication. In addition to being of interest from a biological standpoint, quorum sensing is a potential target for antimicrobial chemotherapy. This unique concept of antimicrobial control relies on reducing the burden of virulence rather than killing the bacteria. It is believed that this approach will not only suppress the development of antibiotic resistance, but will also improve the treatment of refractory infections triggered by multi-drug resistant pathogens. In this paper, we review and track recent progress in studies on AHL inhibitors/modulators from a biological standpoint. It has been discovered that both natural and synthetic compounds can disrupt quorum sensing by a variety of means, such as jamming signal transduction, inhibition of signal production and break-down and trapping of signal compounds. We also focus on the regulatory elements that attenuate quorum sensing activities and discuss their unique properties. Understanding the biological roles of regulatory elements might be useful in developing inhibitor applications and understanding how quorum sensing is controlled.
    Full-text · Article · May 2013 · Frontiers in Microbiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: New N-acyl homoserine lactone analogues, N-acyl-3-amino-5H-furanone derivatives and some 4-halogeno counterparts, were synthesised and tested for their ability to modulate LuxR-dependent bacterial quorum sensing. Both types of analogues proved to be inhibitors, the halogenated compounds being significantly more active. Molecular modelling suggested that the conjugated enamide group induces two preferential conformations leading to specific binding modes. In addition, the presence of the halogen atom could enhance the fitting of the lactone ring through specific interactions with strictly conserved or conservatively replaceable residues in the LuxR protein family, namely Asp79, Trp94 and Ile81.
    Full-text · Article · Jul 2008 · Bioorganic & medicinal chemistry letters
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, we investigated the inhibition of the Lux quorum-sensing system by N-acyl cyclopentylamine (Cn-CPA). The Lux quorum-sensing system regulates luminescence gene expression in Vibrio fischeri. We have already reported on the synthesis of Cn-CPA and their abilities as inhibitors of the quorum-sensing systems in Pseudomonas aeruginosa and Serratia marcescens. In the case of Pseudomonas aeruginosa (Las and Rhl quorum-sensing system) and Serratia marcescens (Spn quorum-sensing system), specific Cn-CPA with a particular acyl chain length showed the strongest inhibitory effect. In the case of the Lux quorum-sensing system, it was found that several kinds of Cn-CPA with a range from C5 to C10 showed similar strong inhibitory effects. Moreover, the inhibitory effect of Cn-CPA on the Lux quorum-sensing system was stronger than that of halogenated furanone, a natural quorum-sensing inhibitor.
    Full-text · Article · Jan 2009 · Acta Biochimica et Biophysica Sinica
Show more