Structure‐Based Discovery and Experimental Verification of Novel AI‐2 Quorum Sensing Inhibitors against Vibrio harveyi

Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI‐2 quorum sensing pathway is found in both Gram‐positive and Gram‐negative bacteria. Therefore, antagonizing AI‐2 quorum sensing is a possible approach to modifying bacterial behaviour. However, efforts in developing inhibitors of AI‐2‐mediated quorum sensing are especially lacking. High‐throughput virtual screening using the V. harveyi LuxP crystal structure identified two compounds that were found to antagonize AI‐2‐mediated quorum sensing in V. harveyi without cytotoxicity. The sulfone functionality of these inhibitors was identified as critical to their ability to mimic the natural ligand in their interactions with Arg 215 and Arg 310 of the active site.

[1]  K. Sonomoto,et al.  Purification, Identification, and Effective Production of a Peptide Antibiotic Produced by Lactococcus lactis IO‐1 (JCM 7638) , 1998, Annals of the New York Academy of Sciences.

[2]  W. Bentley,et al.  Enterohemorrhagic Escherichia coli Biofilms Are Inhibited by 7-Hydroxyindole and Stimulated by Isatin , 2007, Applied and Environmental Microbiology.

[3]  B. Bassler,et al.  Quorum sensing in bacteria. , 2001, Annual review of microbiology.

[4]  Peter G. Schultz,et al.  Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines , 2007, Nature.

[5]  Bonnie L. Bassler,et al.  Bacterial Small-Molecule Signaling Pathways , 2006, Science.

[6]  J M Thornton,et al.  LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. , 1995, Protein engineering.

[7]  Minyong Li,et al.  Pyrogallol and its analogs can antagonize bacterial quorum sensing in Vibrio harveyi. , 2008, Bioorganic & medicinal chemistry letters.

[8]  B. Bassler,et al.  Intercellular signalling in Vibrio harveyi: sequence and function of genes regulating expression of luminescence , 1993, Molecular microbiology.

[9]  E. Greenberg,et al.  Cross-species induction of luminescence in the quorum-sensing bacterium Vibrio harveyi , 1997, Journal of bacteriology.

[10]  T. B. Rasmussen,et al.  Quorum sensing inhibitors: a bargain of effects. , 2006, Microbiology.

[11]  L. Soulère,et al.  Synthesis and Biological Evaluation of the Trifluoromethyl Analog of (4S)‐4,5‐Dihydroxy‐2,3‐pentanedione (DPD) , 2006 .

[12]  K. Janda,et al.  Quorum sensing in Vibrio harveyi: probing the specificity of the LuxP binding site. , 2005, Bioorganic & medicinal chemistry letters.

[13]  Bonnie L. Bassler,et al.  Interference with AI-2-mediated bacterial cell–cell communication , 2005, Nature.

[14]  D. Frank Hsu,et al.  Consensus Scoring Criteria for Improving Enrichment in Virtual Screening , 2005, J. Chem. Inf. Model..

[15]  Gennady Verkhivker,et al.  Deciphering common failures in molecular docking of ligand-protein complexes , 2000, J. Comput. Aided Mol. Des..

[16]  M. Surette,et al.  Communication in bacteria: an ecological and evolutionary perspective , 2006, Nature Reviews Microbiology.

[17]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[18]  L. Soulère,et al.  Ac2-DPD, the bis-(O)-acetylated derivative of 4,5-dihydroxy-2,3-pentanedione (DPD) is a convenient stable precursor of bacterial quorum sensing autoinducer AI-2. , 2007, Bioorganic & medicinal chemistry letters.

[19]  P. Dunlap,et al.  Quorum regulation of luminescence in Vibrio fischeri. , 1999, Journal of molecular microbiology and biotechnology.

[20]  A. Lemme,et al.  Analysing traces of autoinducer-2 requires standardization of the Vibrio harveyi bioassay , 2007, Analytical and bioanalytical chemistry.

[21]  Todd J. A. Ewing,et al.  DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases , 2001, J. Comput. Aided Mol. Des..

[22]  Dacheng Ren,et al.  Differential gene expression shows natural brominated furanones interfere with the autoinducer-2 bacterial signaling system of Escherichia coli. , 2004, Biotechnology and bioengineering.

[23]  Gisbert Schneider,et al.  Virtual screening and fast automated docking methods. , 2002, Drug discovery today.

[24]  Miklos Feher,et al.  Consensus scoring for protein-ligand interactions. , 2006, Drug discovery today.

[25]  N. A. Whitehead,et al.  Quorum-sensing in Gram-negative bacteria. , 2001, FEMS microbiology reviews.

[26]  R. Raffa,et al.  Bacterial Communication (“Quorum Sensing”) via Ligands and Receptors: A Novel Pharmacologic Target for the Design of Antibiotic Drugs , 2005, Journal of Pharmacology and Experimental Therapeutics.

[27]  Minyong Li,et al.  Computational studies of H5N1 hemagglutinin binding with SA-α-2, 3-Gal and SA-α-2, 6-Gal , 2006 .

[28]  T. Wood,et al.  Inhibition of biofilm formation and swarming of Escherichia coli by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. , 2001, Environmental microbiology.

[29]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[30]  Juan E. González,et al.  Messing with Bacterial Quorum Sensing , 2006, Microbiology and Molecular Biology Reviews.

[31]  A furanosyl-carbonate autoinducer in cell-to-cell communication of V. harveyi. , 2005, Chemical communications.

[32]  Kim R Hardie,et al.  LuxS and autoinducer-2: their contribution to quorum sensing and metabolism in bacteria. , 2003, Advances in applied microbiology.

[33]  B. Bassler,et al.  Structural identification of a bacterial quorum-sensing signal containing boron , 2002, Nature.

[34]  S. Papson,et al.  “Model” , 1981 .

[35]  R. Aharoni,et al.  Oxazaborolidine derivatives inducing autoinducer-2 signal transduction in Vibrio harveyi. , 2008, Bioorganic & medicinal chemistry.

[36]  I. Muegge.  Selection criteria for drug‐like compounds , 2003, Medicinal research reviews.

[37]  S. Pillai,et al.  Identification of poultry meat-derived fatty acids functioning as quorum sensing signal inhibitors to autoinducer-2 (AI-2). , 2007, Journal of food science.

[38]  Paul Stoodley,et al.  Biofilm formation and dispersal and the transmission of human pathogens. , 2005, Trends in microbiology.

[39]  J. Thornton,et al.  Satisfying hydrogen bonding potential in proteins. , 1994, Journal of molecular biology.

[40]  Shawn R Campagna,et al.  Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2. , 2004, Molecular cell.

[41]  Minyong Li,et al.  Identification of boronic acids as antagonists of bacterial quorum sensing in Vibrio harveyi. , 2008, Biochemical and biophysical research communications.

[42]  Bonnie L Bassler,et al.  LuxS quorum sensing: more than just a numbers game. , 2003, Current opinion in microbiology.

[43]  Minyong Li,et al.  Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain , 2007, Journal of molecular modeling.

[44]  T. Wood,et al.  Differential Gene Expression for Investigation of Escherichia coli Biofilm Inhibition by Plant Extract Ursolic Acid , 2005, Applied and Environmental Microbiology.

[45]  Irwin D. Kuntz,et al.  Development and validation of a modular, extensible docking program: DOCK 5 , 2006, J. Comput. Aided Mol. Des..

[46]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[47]  M Rarey,et al.  Detailed analysis of scoring functions for virtual screening. , 2001, Journal of medicinal chemistry.

[48]  Christopher W. Murray,et al.  Empirical scoring functions. II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model , 1998, J. Comput. Aided Mol. Des..

[49]  Paul D Lyne,et al.  Structure-based virtual screening: an overview. , 2002, Drug discovery today.

[50]  J. Bajorath,et al.  Docking and scoring in virtual screening for drug discovery: methods and applications , 2004, Nature Reviews Drug Discovery.

[51]  Jürgen Bajorath,et al.  Integration of virtual and high-throughput screening , 2002, Nature Reviews Drug Discovery.

[52]  Minyong Li,et al.  Discovery of the first SecA inhibitors using structure-based virtual screening. , 2008, Biochemical and biophysical research communications.

[53]  Tudor I. Oprea,et al.  Virtual and biomolecular screening converge on a selective agonist for GPR30 , 2006, Nature chemical biology.

[54]  T. B. Rasmussen,et al.  Quorum-sensing inhibitors as anti-pathogenic drugs. , 2006, International journal of medical microbiology : IJMM.

[55]  B. Bassler,et al.  Quorum sensing: cell-to-cell communication in bacteria. , 2005, Annual review of cell and developmental biology.

[56]  E. Gilbert,et al.  Subinhibitory concentrations of cinnamaldehyde interfere with quorum sensing , 2006, Letters in applied microbiology.

[57]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[58]  J. A. Grant,et al.  Gaussian docking functions. , 2003, Biopolymers.

[59]  Shawn R Campagna,et al.  An expeditious synthesis of DPD and boron binding studies. , 2005, Organic letters.