Synthetic Quorum Sensing Inhibitors: Signal Analogues

  • Dimpy Kalia


Bacterial cells possess a unique ability to communicate with each other by utilizing small organic molecules they synthesize. This phenomenon is commonly referred to as quorum sensing and plays a major role in orchestrating bacterial virulence and in the development of bacterial resistance to antibiotics. Therefore, synthetic small organic molecules that interfere with bacterial quorum-sensing networks have a tremendous potential to serve as antibacterial agents. This strategy is especially desirable as it may lead to developing antibacterial agents that operate by imposing lesser selective pressure on bacteria to develop resistant strains as compared to traditional antibiotics which have given rise to highly drug-resistant bacterial strains that have become a major global threat to human health. The development of such synthetic quorum-sensing inhibitors is the major focus of several academic and industrial research laboratories all over the world. This chapter outlines some of the highlights of these efforts with a major emphasis on summarizing the key discoveries pertaining to the structure-activity relationships of the compounds tested. I anticipate that this compendium will serve as a guideline for the design and discovery of new quorum-sensing inhibitors for antibacterial therapeutic applications.


Acyl Chain Quorum Sense Antagonistic Activity Agonistic Activity Lactone Ring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alfaro JF, Zhang T, Wynn DP, Karschner EL, Zhou ZS (2004) Synthesis of LuxS inhibitors targeting bacterial cell-cell communication. Org Lett 6:3043–3046PubMedCrossRefGoogle Scholar
  2. Bjarnsholt T, Jensen PO, Burmolle M, Hentzer M, Haagensen JA, Hougen HP, Calum H, Madsen KG, Moser C, Molin S, Hoiby N, Givskov M (2005) Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. Microbiology 151:373–383PubMedCrossRefGoogle Scholar
  3. Boukraa M, Sabbah M, Soulere L, EL Efrit ML, Queneau Y, Doutheau A (2011) AHL-dependent quorum sensing inhibition: synthesis and biological evaluation of alpha-(N-alkyl-carboxamide)-gamma-butyrolactones and alpha-(N-alkyl-sulfonamide)-gamma-butyrolactones. Bioorg Med Chem Lett 21:6876–6879PubMedCrossRefGoogle Scholar
  4. Castang S, Chantegrel B, Deshayes C, Dolmazon R, Gouet P, Haser R, Reverchon S, Nasser W, Hugouvieux-Cotte-Pattat N, Doutheau A (2004) N-Sulfonyl homoserine lactones as antagonists of bacterial quorum sensing. Bioorg Med Chem Lett 14:5145–5149PubMedCrossRefGoogle Scholar
  5. Cegelski L, Marshall GR, Eldridge GR, Hultgren SJ (2008) The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6:17–27PubMedCrossRefPubMedCentralGoogle Scholar
  6. Clatworthy AE, Pierson E, Hung DT (2007) Targeting virulence: a new paradigm for antimicrobial therapy. Nat Chem Biol 3:541–548PubMedCrossRefGoogle Scholar
  7. Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP (1998) The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 280:295–298PubMedCrossRefGoogle Scholar
  8. Deng Y, Wu J, Tao F, Zhang LH (2011) Listening to a new language: DSF-based quorum sensing in Gram-negative bacteria. Chem Rev 111:160–173PubMedCrossRefGoogle Scholar
  9. Dubern JF, Diggle SP (2008) Quorum sensing by 2-alkyl-4-quinolones in Pseudomonas aeruginosa and other bacterial species. Mol Biosyst 4:882–888PubMedCrossRefGoogle Scholar
  10. Eberhard A, Widrig CA, Mcbath P, Schineller JB (1986) Analogs of the autoinducer of bioluminescence in Vibrio fischeri. Arch Microbiol 146:35–40PubMedCrossRefGoogle Scholar
  11. Frezza M, Castang S, Estephane J, Soulere L, Deshayes C, Chantegrel B, Nasser W, Queneau Y, Reverchon S, Doutheau A (2006) Synthesis and biological evaluation of homoserine lactone derived ureas as antagonists of bacterial quorum sensing. Bioorg Med Chem 14:4781–4791PubMedCrossRefGoogle Scholar
  12. Frezza M, Soulere L, Reverchon S, Guiliani N, Jerez C, Queneau Y, Doutheau A (2008) Synthetic homoserine lactone-derived sulfonylureas as inhibitors of Vibrio fischeri quorum sensing regulator. Bioorg Med Chem 16:3550–3556PubMedCrossRefGoogle Scholar
  13. Galloway WR, Hodgkinson JT, Bowden SD, Welch M, Spring DR (2011) Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways. Chem Rev 111:28–67PubMedCrossRefGoogle Scholar
  14. Ganin H, Tang X, Meijler MM (2009) Inhibition of Pseudomonas aeruginosa quorum sensing by AI-2 analogs. Bioorg Med Chem Lett 19:3941–3944PubMedCrossRefGoogle Scholar
  15. Geske GD, Wezeman RJ, Siegel AP, Blackwell HE (2005) Small molecule inhibitors of bacterial quorum sensing and biofilm formation. J Am Chem Soc 127:12762–12763PubMedCrossRefGoogle Scholar
  16. Geske GD, O’neill JC, Miller DM, Mattmann ME, Blackwell HE (2007) Modulation of bacterial quorum sensing with synthetic ligands: systematic evaluation of N-acylated homoserine lactones in multiple species and new insights into their mechanisms of action. J Am Chem Soc 129:13613–13625PubMedCrossRefPubMedCentralGoogle Scholar
  17. Geske GD, Mattmann ME, Blackwell HE (2008a) Evaluation of a focused library of N-aryl L-homoserine lactones reveals a new set of potent quorum sensing modulators. Bioorg Med Chem Lett 18:5978–5981PubMedCrossRefPubMedCentralGoogle Scholar
  18. Geske GD, O’neill JC, Blackwell HE (2008b) Expanding dialogues: from natural autoinducers to non-natural analogues that modulate quorum sensing in Gram-negative bacteria. Chem Soc Rev 37:1432–1447PubMedCrossRefPubMedCentralGoogle Scholar
  19. Givskov MNJ (2003) Compounds and methods for controlling bacterial virulence. Patent No. WO2003106445 A1 Google Scholar
  20. Givskov M, de Nys R, Manefield M, Gram L, Maximilien R, Eberl L, Molin S, Steinberg PD, Kjelleberg S (1996) Eukaryotic interference with homoserine lactone-mediated prokaryotic signalling. J Bacteriol 178:6618–6622PubMedPubMedCentralGoogle Scholar
  21. Globisch D, Lowery CA, Mccague KC, Janda KD (2012) Uncharacterized 4,5-dihydroxy-2,3-pentanedione (DPD) molecules revealed through NMR spectroscopy: implications for a greater signaling diversity in bacterial species. Angew Chem Int Ed Engl 51:4204–4208PubMedCrossRefPubMedCentralGoogle Scholar
  22. Gopishetty B, Zhu J, Rajan R, Sobczak AJ, Wnuk SF, Bell CE, Pei D (2009) Probing the catalytic mechanism of S-ribosylhomocysteinase (LuxS) with catalytic intermediates and substrate analogues. J Am Chem Soc 131:1243–1250PubMedCrossRefPubMedCentralGoogle Scholar
  23. Guo M, Gamby S, Zheng Y, Sintim HO (2013) Small molecule inhibitors of AI-2 signaling in bacteria: state-of-the-art and future perspectives for anti-quorum sensing agents. Int J Mol Sci 14:17694–17728PubMedCrossRefPubMedCentralGoogle Scholar
  24. Gutierrez JA, Crowder T, Rinaldo-Matthis A, Ho MC, Almo SC, Schramm VL (2009) Transition state analogs of 5′-methylthioadenosine nucleosidase disrupt quorum sensing. Nat Chem Biol 5:251–257PubMedCrossRefPubMedCentralGoogle Scholar
  25. Ha JH, Eo Y, Grishaev A, Guo M, Smith JA, Sintim HO, Kim EH, Cheong HK, Bentley WE, Ryu KS (2013) Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition. J Am Chem Soc 135:15526–15535PubMedCrossRefGoogle Scholar
  26. Haapalainen AM, Thomas K, Tyler PC, Evans GB, Almo SC, Schramm VL (2013) Salmonella enterica MTAN at 1.36 A resolution: a structure-based design of tailored transition state analogs. Structure 21:963–974PubMedCrossRefPubMedCentralGoogle Scholar
  27. Hentzer M, Givskov M (2003) Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J Clin Invest 112:1300–1307PubMedCrossRefPubMedCentralGoogle Scholar
  28. Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB, Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P, Manefield M, Costerton JW, Molin S, Eberl L, Steinberg P, Kjelleberg S, Hoiby N, Givskov M (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22:3803–3815PubMedCrossRefPubMedCentralGoogle Scholar
  29. Ilangovan A, Fletcher M, Rampioni G, Pustelny C, Rumbaugh K, Heeb S, Camara M, Truman A, Chhabra SR, Emsley J, Williams P (2013) Structural basis for native agonist and synthetic inhibitor recognition by the Pseudomonas aeruginosa quorum sensing regulator PqsR (MvfR). PLoS Pathog 9:e1003508PubMedCrossRefPubMedCentralGoogle Scholar
  30. Ishida T, Ikeda T, Takiguchi N, Kuroda A, Ohtake H, Kato J (2007) Inhibition of quorum sensing in Pseudomonas aeruginosa by N-acyl cyclopentylamides. Appl Environ Microbiol 73:3183–3188PubMedCrossRefPubMedCentralGoogle Scholar
  31. Jimenez PN, Koch G, Thompson JA, Xavier KB, Cool RH, Quax WJ (2012) The multiple signaling systems regulating virulence in Pseudomonas aeruginosa. Microbiol Mol Biol Rev 76:46–65PubMedCrossRefGoogle Scholar
  32. Jog GJ, Igarashi J, Suga H (2006) Stereoisomers of P. aeruginosa autoinducer analog to probe the regulator binding site. Chem Biol 13:123–128PubMedCrossRefGoogle Scholar
  33. Kline T, Bowman J, Iglewski BH, de Kievit T, Kakai Y, Passador L (1999) Novel synthetic analogs of the Pseudomonas autoinducer. Bioorg Med Chem Lett 9:3447–3452PubMedCrossRefGoogle Scholar
  34. Lewis K (2013) Platforms for antibiotic discovery. Nat Rev Drug Discov 12:371–387PubMedCrossRefGoogle Scholar
  35. Liu D, Lepore BW, Petsko GA, Thomas PW, Stone EM, Fast W, Ringe D (2005) Three-dimensional structure of the quorum-quenching N-acyl homoserine lactone hydrolase from Bacillus thuringiensis. Proc Natl Acad Sci U S A 102:11882–11887PubMedCrossRefPubMedCentralGoogle Scholar
  36. Liu CF, Liu D, Momb J, Thomas PW, Lajoie A, Petsko GA, Fast W, Ringe D (2013) A phenylalanine clamp controls substrate specificity in the quorum-quenching metallo-gamma-lactonase from Bacillus thuringiensis. Biochemistry 52:1603–1610PubMedCrossRefPubMedCentralGoogle Scholar
  37. Lowery CA, Mckenzie KM, Qi L, Meijler MM, Janda KD (2005) Quorum sensing in Vibrio harveyi: probing the specificity of the LuxP binding site. Bioorg Med Chem Lett 15:2395–2398PubMedCrossRefGoogle Scholar
  38. Lowery CA, Dickerson TJ, Janda KD (2008a) Interspecies and interkingdom communication mediated by bacterial quorum sensing. Chem Soc Rev 37:1337–1346PubMedCrossRefGoogle Scholar
  39. Lowery CA, Park J, Kaufmann GF, Janda KD (2008b) An unexpected switch in the modulation of AI-2-based quorum sensing discovered through synthetic 4,5-dihydroxy-2,3-pentanedione analogues. J Am Chem Soc 130:9200–9201PubMedCrossRefPubMedCentralGoogle Scholar
  40. Lowery CA, Matamouros S, Niessen S, Zhu J, Scolnick J, Lively JM, Cravatt BF, Miller SI, Kaufmann GF, Janda KD (2013) A chemical biology approach to interrogate quorum-sensing regulated behaviors at the molecular and cellular level. Chem Biol 20:903–911PubMedCrossRefPubMedCentralGoogle Scholar
  41. Manefield M, de Nys R, Kumar N, Read R, Givskov M, Steinberg P, Kjelleberg S (1999) Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein. Microbiology 145(Pt 2):283–291PubMedCrossRefGoogle Scholar
  42. Marra A (2004) Can virulence factors be viable antibacterial targets? Expert Rev Anti Infect Ther 2:61–72PubMedCrossRefGoogle Scholar
  43. Mattmann ME, Geske GD, Worzalla GA, Chandler JR, Sappington KJ, Greenberg EP, Blackwell HE (2008) Synthetic ligands that activate and inhibit a quorum-sensing regulator in Pseudomonas aeruginosa. Bioorg Med Chem Lett 18:3072–3075PubMedCrossRefGoogle Scholar
  44. Mcinnis CE, Blackwell HE (2011) Thiolactone modulators of quorum sensing revealed through library design and screening. Bioorg Med Chem 19:4820–4828PubMedCrossRefPubMedCentralGoogle Scholar
  45. Meijler MM, Hom LG, Kaufmann GF, Mckenzie KM, Sun C, Moss JA, Matsushita M, Janda KD (2004) Synthesis and biological validation of a ubiquitous quorum-sensing molecule. Angew Chem Int Ed Engl 43:2106–2108PubMedCrossRefGoogle Scholar
  46. Ng WL, Bassler BL (2009) Bacterial quorum-sensing network architectures. Annu Rev Genet 43:197–222PubMedCrossRefGoogle Scholar
  47. Novick RP, Muir TW (1999) Virulence gene regulation by peptides in Staphylococci and other Gram-positive bacteria. Curr Opin Microbiol 2:40–45PubMedCrossRefGoogle Scholar
  48. Olsen JA, Severinsen R, Rasmussen TB, Hentzer M, Givskov M, Nielsen J (2002) Synthesis of new 3- and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers. Bioorg Med Chem Lett 12:325–328PubMedCrossRefGoogle Scholar
  49. Parsek MR, Val DL, Hanzelka BL, Cronan JE Jr, Greenberg EP (1999) Acyl homoserine-lactone quorum-sensing signal generation. Proc Natl Acad Sci U S A 96:4360–4365PubMedCrossRefPubMedCentralGoogle Scholar
  50. Parveen N, Cornell KA (2011) Methylthioadenosine/S-adenosylhomocysteine nucleosidase, a critical enzyme for bacterial metabolism. Mol Microbiol 79:7–20PubMedCrossRefPubMedCentralGoogle Scholar
  51. Passador L, Tucker KD, Guertin KR, Journet MP, Kende AS, Iglewski BH (1996) Functional analysis of the Pseudomonas aeruginosa autoinducer PAI. J Bacteriol 178:5995–6000PubMedPubMedCentralGoogle Scholar
  52. Patani GA, Lavoie EJ (1996) Bioisosterism: a rational approach in drug design. Chem Rev 96:3147–3176PubMedCrossRefGoogle Scholar
  53. Pereira CS, Thompson JA, Xavier KB (2013) AI-2-mediated signalling in bacteria. FEMS Microbiol Rev 37:156–181PubMedGoogle Scholar
  54. Rasmussen TB, Givskov M (2006) Quorum-sensing inhibitors as anti-pathogenic drugs. Int J Med Microbiol 296:149–161PubMedCrossRefGoogle Scholar
  55. Rasmussen TB, Bjarnsholt T, Skindersoe ME, Hentzer M, Kristoffersen P, Kote M, Nielsen J, Eberl L, Givskov M (2005) Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol 187:1799–1814PubMedCrossRefPubMedCentralGoogle Scholar
  56. Reverchon S, Chantegrel B, Deshayes C, Doutheau A, Cotte-Pattat N (2002) New synthetic analogues of N-acyl homoserine lactones as agonists or antagonists of transcriptional regulators involved in bacterial quorum sensing. Bioorg Med Chem Lett 12:1153–1157PubMedCrossRefGoogle Scholar
  57. Schaefer AL, Hanzelka BL, Eberhard A, Greenberg EP (1996) Quorum sensing in Vibrio fischeri: probing autoinducer-LuxR interactions with autoinducer analogs. J Bacteriol 178:2897–2901PubMedPubMedCentralGoogle Scholar
  58. Schuster M, Sexton DJ, Diggle SP, Greenberg EP (2013) Acyl-homoserine lactone quorum sensing: from evolution to application. Annu Rev Microbiol 67:43–63PubMedCrossRefGoogle Scholar
  59. Shen G, Rajan R, Zhu J, Bell CE, Pei D (2006) Design and synthesis of substrate and intermediate analogue inhibitors of S-ribosylhomocysteinase. J Med Chem 49:3003–3011PubMedCrossRefGoogle Scholar
  60. Sintim HO, Smith JA, Wang J, Nakayama S, Yan L (2010) Paradigm shift in discovering next-generation anti-infective agents: targeting quorum sensing, c-di-GMP signaling and biofilm formation in bacteria with small molecules. Future Med Chem 2:1005–1035PubMedCrossRefGoogle Scholar
  61. Smith KM, Bu Y, Suga H (2003a) Induction and inhibition of Pseudomonas aeruginosa quorum sensing by synthetic autoinducer analogs. Chem Biol 10:81–89PubMedCrossRefGoogle Scholar
  62. Smith KM, Bu Y, Suga H (2003b) Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosa autoinducer. Chem Biol 10:563–571PubMedCrossRefGoogle Scholar
  63. Smith JA, Wang J, Nguyen-Mau SM, Lee V, Sintim HO (2009) Biological screening of a diverse set of AI-2 analogues in Vibrio harveyi suggests that receptors which are involved in synergistic agonism of AI-2 and analogues are promiscuous. Chem Commun (Camb) 45:7033–7035CrossRefGoogle Scholar
  64. Sturme MH, Kleerebezem M, Nakayama J, Akkermans AD, Vaugha EE, de Vos WM (2002) Cell to cell communication by autoinducing peptides in gram-positive bacteria. Antonie Van Leeuwenhoek 81:233–243PubMedCrossRefGoogle Scholar
  65. Thomas K, Haapalainen AM, Burgos ES, Evans GB, Tyler PC, Gulab S, Guan R, Schramm VL (2012) Femtomolar inhibitors bind to 5′-methylthioadenosine nucleosidases with favorable enthalpy and entropy. Biochemistry 51:7541–7550PubMedCrossRefGoogle Scholar
  66. von Nussbaum F, Brands M, Hinzen B, Weigand S, Habich D (2006) Antibacterial natural products in medicinal chemistry–exodus or revival? Angew Chem Int Ed Engl 45:5072–5129CrossRefGoogle Scholar
  67. Waters CM, Bassler BL (2005) Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol 21:319–346PubMedCrossRefGoogle Scholar
  68. Watson WT, Minogue TD, Val DL, von Bodman SB, Churchill ME (2002) Structural basis and specificity of acyl-homoserine lactone signal production in bacterial quorum sensing. Mol Cell 9:685–694PubMedCrossRefGoogle Scholar
  69. Wnuk SF, Robert J, Sobczak AJ, Meyers BP, Malladi VL, Zhu J, Gopishetty B, Pei D (2009) Inhibition of S-ribosylhomocysteinase (LuxS) by substrate analogues modified at the ribosyl C-3 position. Bioorg Med Chem 17:6699–6706PubMedCrossRefPubMedCentralGoogle Scholar
  70. Worthington RJ, Melander C (2012) Deconvoluting interspecies bacterial communication. Angew Chem Int Ed Engl 51:6314–6315PubMedCrossRefGoogle Scholar
  71. Wu H, Song Z, Hentzer M, Andersen JB, Molin S, Givskov M, Hoiby N (2004) Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J Antimicrob Chemother 53:1054–1061PubMedCrossRefGoogle Scholar
  72. Zhang RG, Pappas KM, Brace JL, Miller PC, Oulmassov T, Molyneaux JM, Anderson JC, Bashkin JK, Winans SC, Joachimiak A (2002) Structure of a bacterial quorum-sensing transcription factor complexed with pheromone and DNA. Nature 417:971–974PubMedCrossRefGoogle Scholar
  73. Zhu J, Beaber JW, More MI, Fuqua C, Eberhard A, Winans SC (1998) Analogs of the autoinducer 3-oxooctanoyl-homoserine lactone strongly inhibit activity of the TraR protein of Agrobacterium tumefaciens. J Bacteriol 180:5398–5405PubMedPubMedCentralGoogle Scholar
  74. Zhu J, Hixon MS, Globisch D, Kaufmann GF, Janda KD (2013) Mechanistic insights into the LsrK kinase required for autoinducer-2 quorum sensing activation. J Am Chem Soc 135:7827–7830PubMedCrossRefPubMedCentralGoogle Scholar
  75. Zou Y, Nair SK (2009) Molecular basis for the recognition of structurally distinct autoinducer mimics by the Pseudomonas aeruginosa LasR quorum-sensing signaling receptor. Chem Biol 16:961–970PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer India 2015

Authors and Affiliations

  1. 1.DST-INSPIRE Faculty, Department of ChemistryUniversity of PunePuneIndia

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