Lichen secondary metabolite evernic acid as potential quorum sensing inhibitor against Pseudomonas aeruginosa

  • Barış Gökalsın
  • Nüzhet Cenk SesalEmail author
Original Paper


Cystic Fibrosis is a genetic disease and it affects the respiratory and digestive systems. Pseudomonas aeruginosa infections in Cystic Fibrosis are presented as the main cause for high mortality and morbidity rates. Pseudomonas aeruginosa populations can regulate their virulence gene expressions via the bacterial communication system: quorum sensing. Inhibition of quorum sensing by employing quorum sensing inhibitors can leave the bacteria vulnerable. Therefore, determining natural sources to obtain potential quorum sensing inhibitors is essential. Lichens have ethnobotanical value for their medicinal properties and it is possible that their secondary metabolites have quorum sensing inhibitor properties. This study aims to investigate an alternative treatment approach by utilizing lichen secondary metabolite evernic acid to reduce the expressions of Pseudomonas aeruginosa virulence factors by inhibiting quorum sensing. For this purpose, fluorescent monitor strains were utilized for quorum sensing inhibitor screens and quantitative reverse-transcriptase PCR analyses were conducted for comparison. Results indicate that evernic acid is capable of inhibiting Pseudomonas aeruginosa quorum sensing systems.


Quorum sensing Pseudomonasaeruginosa Lichen secondary metabolites Evernic acid 



We thank Tim Holm Jakobsen and Michael Givskov for providing us the monitor strains. This study was funded by the projects: TUBITAK 113S306 (COST FA1202) and BAPKO FEN-A-130515-0177.


  1. Acikgoz B, Karalti I, Ersoz M, Coskun ZM, Cobanoglu G, Sesal C (2013) Screening of antimicrobial activity and cytotoxic effects of two Cladonia species. Z Naturforsch C 68:191–197CrossRefGoogle Scholar
  2. Al-Ani I, Zimmermann S, Reichling J, Wink M (2015) Pharmacological synergism of bee venom and melittin with antibiotics and plant secondary metabolites against multi-drug resistant microbial pathogens. Phytomedicine 22:245–255. doi: 10.1016/j.phymed.2014.11.019 CrossRefGoogle Scholar
  3. Azimi H, Khakshur AA, Aghdasi I, Fallah-Tafti M, Abdollahi M (2012) A review of animal and human studies for management of benign prostatic hyperplasia with natural products: perspective of new pharmacological agents. Inflamm Allergy Drug Targets 11:207–221CrossRefGoogle Scholar
  4. Basile A et al (2015) Antiproliferative, antibacterial and antifungal activity of the lichen Xanthoria parietina and its secondary metabolite parietin. Int J Mol Sci 16:7861–7875CrossRefGoogle Scholar
  5. Bassler B (2015) Manipulating quorum sensing to control bacterial pathogenicity. FASEB J 29(Suppl 1):88-1Google Scholar
  6. Bhattarai HD, Paudel B, Hong SG, Lee HK, Yim JH (2008) Thin layer chromatography analysis of antioxidant constituents of lichens from Antarctica. J Nat Med 62:481–484CrossRefGoogle Scholar
  7. Bjarnsholt T, van Gennip M, Jakobsen TH, Christensen LD, Jensen PO, Givskov M (2010) In vitro screens for quorum sensing inhibitors and in vivo confirmation of their effect. Nat Protoc 5:282–293. doi: 10.1038/nprot.2009.205 CrossRefGoogle Scholar
  8. Boor KJ (2006) Bacterial stress responses: what doesn’t kill them can make them stronger. PLoS Biol 4:18–20. doi: 10.1371/journal.pbio.0040023 CrossRefGoogle Scholar
  9. Brackman G, Coenye T (2015) Quorum sensing ınhibitors as anti-biofilm agents. Curr Pharm Des 21:5–11CrossRefGoogle Scholar
  10. Caldas RR, Boisrame S (2015) Upper aero-digestive contamination by Pseudomonas aeruginosa and implications in Cystic Fibrosis. J Cystic Fibros 14:6–15. doi: 10.1016/j.jcf.2014.04.008 CrossRefGoogle Scholar
  11. De Kievit T (2009) Quorum sensing in Pseudomonas aeruginosa biofilms. Environ Microbiol 11:279–288CrossRefGoogle Scholar
  12. Deduke C, Timsina B, Piercey-Normore MD (2012) Effect of environmental change on secondary metabolite production in lichen-forming fungi. In: Young S (ed) International perspectives on global environmental change. InTech, Rejika, CroatiaGoogle Scholar
  13. Diggle SP, Winzer K, Chhabra SR, Chhabra SR, Worrall KE, Camara M, Williams P (2003) The Pseudomonas aeruginosa quinolone signal molecule overcomes the cell density-dependency of the quorum sensing hierarchy, regulates rhl-dependent genes at the onset of stationary phase and can be produced in the absence of LasR. Mol Microbiol 50:29–43. doi: 10.1046/j.1365-2958.2003.03672.x CrossRefGoogle Scholar
  14. Fernandez-Moriano C, Gomez-Serranillos MP, Crespo A (2016) Antioxidant potential of lichen species and their secondary metabolites. A systematic review. Pharm Biol 54:1–17. doi: 10.3109/13880209.2014.1003354 CrossRefGoogle Scholar
  15. Fux CA, Costerton JW, Stewart PS, Stoodley P (2005) Survival strategies of infectious biofilms. Trends Microbiol 13:34–40. doi: 10.1016/j.tim.2004.11.010 CrossRefGoogle Scholar
  16. Girard G, Bloemberg GV (2008) Central role of quorum sensing in regulating the production of pathogenicity factors in Pseudomonas aeruginosa. Future Microbiol 3:97–106. doi: 10.2217/17460913.3.1.97 CrossRefGoogle Scholar
  17. Hentzer M et al (2002) Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology-Sgm 148:87–102CrossRefGoogle Scholar
  18. Hentzer M, Eberl L, Nielsen J, Givskov M (2003a) Quorum sensing—a novel target for the treatment of biofilm infections. Biodrugs 17:241–250. doi: 10.2165/00063030-200317040-00003 CrossRefGoogle Scholar
  19. Hentzer M et al (2003b) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22:3803–3815. doi: 10.1093/emboj/cdg366 CrossRefGoogle Scholar
  20. Holloway BW, Morgan AF (1986) Genome organization in Pseudomonas. Annu Rev Microbiol 40:79–105. doi: 10.1146/annurev.micro.40.1.79 CrossRefGoogle Scholar
  21. Jakobsen TH et al (2012) Food as a source for quorum sensing inhibitors: iberin from horseradish revealed as a quorum sensing inhibitor of Pseudomonas aeruginosa. Appl Environ Microbiol 78:2410–2421. doi: 10.1128/Aem.05992-11 CrossRefGoogle Scholar
  22. Jakobsen TH, Bjarnsholt T, Jensen PO, Givskov M, Hoiby N (2013) Targeting quorum sensing in Pseudomonas aeruginosa biofilms: current and emerging inhibitors. Future Microbiol 8:901–921. doi: 10.2217/fmb.13.57 CrossRefGoogle Scholar
  23. Jones RN, Stilwell MG, Rhomberg PR, Sader HS (2009) Antipseudomonal activity of piperacillin/tazobactam: more than a decade of experience from the SENTRY Antimicrobial Surveillance Program (1997–2007). Diagn Microbiol Infect Dis 65:331–334. doi: 10.1016/j.diagmicrobio.2009.06.022 CrossRefGoogle Scholar
  24. Lambert ML et al (2011) Clinical outcomes of health-care-associated infections and antimicrobial resistance in patients admitted to European intensive-care units: a cohort study. Lancet Infect Dis 11:30–38. doi: 10.1016/S1473-3099(10)70258-9 CrossRefGoogle Scholar
  25. Lee J, Zhang L (2015) The hierarchy quorum sensing network in Pseudomonas aeruginosa. Protein Cell 6:26–41CrossRefGoogle Scholar
  26. Lee J et al (2013) A cell-cell communication signal integrates quorum sensing and stress response. Nat Chem Biol 9:339–343CrossRefGoogle Scholar
  27. Marijana K, Branislav R (2011) Antibacterial and antifungal activity of different lichens extracts and lichen acid. Res J Biotechnol 6:23–26Google Scholar
  28. McGrath S, Wade DS, Pesci EC (2004) Dueling quorum sensing systems in Pseudomonas aeruginosa control the production of the Pseudomonas quinolone signal (PQS). FEMS Microbiol Lett 230:27–34. doi: 10.1016/S0378-1097(03)00849-8 CrossRefGoogle Scholar
  29. Nash TH (ed) (2008) Lichen biology. Cambridge University Press, CambridgeGoogle Scholar
  30. Nguyen TT et al (2014) Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials. PLoS ONE 9:e111575. doi: 10.1371/journal.pone.0111575 CrossRefGoogle Scholar
  31. Pesci EC, Milbank JB, Pearson JP, McKnight S, Kende AS, Greenberg EP, Iglewski BH (1999) Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc Natl Acad Sci 96:11229–11234CrossRefGoogle Scholar
  32. Pompilio A et al (2013) Antimicrobial and antibiofilm activity of secondary metabolites of lichens against methicillin-resistant Staphylococcus aureus strains from cystic fibrosis patients. Future Microbiol 8:281–292. doi: 10.2217/Fmb.12.142 CrossRefGoogle Scholar
  33. Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K (2013) Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cystic Fibros 12:29–34. doi: 10.1016/j.jcf.2012.06.001 CrossRefGoogle Scholar
  34. Savo V, Joy R, Caneva G, McClatchey WC (2015) Plant selection for ethnobotanical uses on the Amalfi Coast (Southern Italy). J Ethnobiol Ethnomed 11:58. doi: 10.1186/s13002-015-0038-y CrossRefGoogle Scholar
  35. Shannon KP, French GL (2004) Increasing resistance to antimicrobial agents of Gram-negative organisms isolated at a London teaching hospital, 1995–2000. J Antimicrob Chemother 53:818–825. doi: 10.1093/jac/dkh135 CrossRefGoogle Scholar
  36. Shukla V, Joshi GP, Rawat M (2010) Lichens as a potential natural source of bioactive compounds: a review. Phytochem Rev 9:303–314CrossRefGoogle Scholar
  37. Truchado P, Tomas-Barberan FA, Larrosa M, Allende A (2012) Food phytochemicals act as quorum sensing inhibitors reducing production and/or degrading autoinducers of Yersinia enterocolitica and Erwinia carotovora. Food Control 24:78–85. doi: 10.1016/j.foodcont.2011.09.006 CrossRefGoogle Scholar
  38. Yang L, Rybtke MT, Jakobsen TH, Hentzer M, Bjarnsholt T, Givskov M, Tolker-Nielsen T (2009) Computer-aided identification of recognized drugs as Pseudomonas aeruginosa quorum-sensing inhibitors. Antimicrob Agents Chemother 53:2432–2443. doi: 10.1128/Aac.01283-08 CrossRefGoogle Scholar
  39. Zeng Z et al (2008) Virtual screening for novel quorum sensing inhibitors to eradicate biofilm formation of Pseudomonas aeruginosa. Appl Microbiol Biotechnol 79:119–126. doi: 10.1007/s00253-008-1406-5 CrossRefGoogle Scholar
  40. Zhanel GG, Hoban DJ, Schurek K, Karlowsky JA (2004) Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa. Int J Antimicrob Agents 24:529–535. doi: 10.1016/j.ijantimicag.2004.08.003 CrossRefGoogle Scholar
  41. Zhang RG et al (2002) Structure of a bacterial quorum-sensing transcription factor complexed with pheromone and DNA. Nature 417:971–974. doi: 10.1038/nature00833 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.Department of Biology, Faculty of Arts and SciencesMarmara UniversityIstanbulTurkey

Personalised recommendations