C4-alkoxy-HPD: a potent class of synthetic modulators surpassing nature in AI-2 quorum sensing.

Bacteria have developed cell-to-cell communication mechanisms, termed quorum sensing (QS), that regulate bacterial gene expression in a cell population-dependent manner. Autoinducer-2 (AI-2), a class of QS signaling molecules derived from (4S)-4,5-dihydroxy-2,3-pentanedione (DPD), has been identified in both Gram-negative and Gram-positive bacteria. Despite considerable interest in the AI-2 QS system, the biomolecular communication used by distinct bacterial species still remains shrouded. Herein, we report the synthesis and evaluation of a new class of DPD analogues, C4-alkoxy-5-hydroxy-2,3-pentanediones, termed C4-alkoxy-HPDs. Remarkably, two of the analogues were more potent QS agonists than the natural ligand, DPD, in Vibrio harveyi. The findings presented extend insights into ligand-receptor recognition/signaling in the AI-2 mediated QS system.

[1]  Kristina M Smith,et al.  Molecular mechanisms of bacterial quorum sensing as a new drug target. , 2003, Current opinion in chemical biology.

[2]  Fuyuhiko Inagaki,et al.  A new procedure for the preparation of 2-vinylindoles and their [4+2] cycloaddition reaction , 2011 .

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

[4]  C. Maycock,et al.  Stereochemical diversity of AI-2 analogs modulates quorum sensing in Vibrio harveyi and Escherichia coli. , 2012, Bioorganic & medicinal chemistry.

[5]  Kevin L. Griffith,et al.  Measuring beta-galactosidase activity in bacteria: cell growth, permeabilization, and enzyme assays in 96-well arrays. , 2002, Biochemical and biophysical research communications.

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

[7]  Junguk Park,et al.  An unexpected switch in the modulation of AI-2-based quorum sensing discovered through synthetic 4,5-dihydroxy-2,3-pentanedione analogues. , 2008, Journal of the American Chemical Society.

[8]  Minyong Li,et al.  Recent progresses on AI-2 bacterial quorum sensing inhibitors. , 2012, Current medicinal chemistry.

[9]  William E Bentley,et al.  Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogues. , 2012, ACS chemical biology.

[10]  K. Nealson,et al.  Bacterial bioluminescence: Isolation and genetic analysis of functions from Vibrio fischeri , 1983, Cell.

[11]  K. Janda,et al.  Probing autoinducer-2 based quorum sensing: the biological consequences of molecules unable to traverse equilibrium states. , 2011, The Journal of organic chemistry.

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

[13]  W. Bentley,et al.  Synthetic analogs tailor native AI-2 signaling across bacterial species. , 2010, Journal of the American Chemical Society.

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

[15]  M. Meijler,et al.  Inhibition of Pseudomonas aeruginosa quorum sensing by AI-2 analogs. , 2009, Bioorganic & medicinal chemistry letters.

[16]  Kim R Hardie,et al.  LuxS: its role in central metabolism and the in vitro synthesis of 4-hydroxy-5-methyl-3(2H)-furanone. , 2002, Microbiology.

[17]  E. Greenberg,et al.  Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators , 1994, Journal of bacteriology.

[18]  K. Janda,et al.  Medicinal chemistry as a conduit for the modulation of quorum sensing. , 2010, Journal of medicinal chemistry.

[19]  B. Bassler,et al.  Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: sequence and function of genes encoding a second sensory pathway , 1994, Molecular microbiology.

[20]  Thomas Bjarnsholt,et al.  Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. , 2005, Microbiology.

[21]  Kim D Janda,et al.  Uncharacterized 4,5-dihydroxy-2,3-pentanedione (DPD) molecules revealed through NMR spectroscopy: implications for a greater signaling diversity in bacterial species. , 2012, Angewandte Chemie.

[22]  K. Janda,et al.  Revisiting AI-2 quorum sensing inhibitors: direct comparison of alkyl-DPD analogues and a natural product fimbrolide. , 2009, Journal of the American Chemical Society.

[23]  Kim D Janda,et al.  Synthesis and biological validation of a ubiquitous quorum-sensing molecule. , 2004, Angewandte Chemie.

[24]  B. Bassler,et al.  Ligand-Induced Asymmetry in Histidine Sensor Kinase Complex Regulates Quorum Sensing , 2006, Cell.

[25]  Liping Zhao,et al.  LsrR-binding site recognition and regulatory characteristics in Escherichia coli AI-2 quorum sensing , 2009, Cell Research.

[26]  B. Bassler,et al.  Lsr‐mediated transport and processing of AI‐2 in Salmonella typhimurium , 2003, Molecular microbiology.

[27]  Klaus Winzer,et al.  Making 'sense' of metabolism: autoinducer-2, LUXS and pathogenic bacteria , 2005, Nature Reviews Microbiology.

[28]  Jeong Hwan Kim,et al.  Phosphorylation and processing of the quorum-sensing molecule autoinducer-2 in enteric bacteria. , 2007, ACS chemical biology.