In Vivo Studies: Inhibiting Biofilm-Associated Bacterial Infections Using QSIs

Part of the Springer Series on Biofilms book series (BIOFILMS, volume 2)


This chapter reviews animal studies carried out using quorum-sensing inhibitors of Gram-negative and Gram-positive bacterial biofilm infections. Animal studies include the use of biofilm inhibitors to suppress Pseudomonas aeruginosa lung infections in mice, and the use of biofilm inhibitors to suppress antibiotic-resistant staphylococcal infections like methicillin-resistant Staphylococcus aureus in rat graft and central venous catheter models and mouse cellulitis models. The advantages of using biofilm inhibitors over those of conventional antibiotics, and the choice of inhibitor to be used are discussed.


Garlic Extract Tiger Prawn Staphylococcal Strain Chronic Lung Infection Black Tiger Prawn 
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. 1.
    Abraham WR (2006) Controlling biofilms of gram-positive pathogenic bacteria. Curr Med Chem 13:1509–1524PubMedCrossRefGoogle Scholar
  2. 2.
    Anguita-Alonso P, Giacometti A, Cirioni O, Ghiselli R, Orlando F, Saba V, Scalise G, Sevo M, Tuzova M, Patel R, Balaban N (2006) RNAIII-inhibiting peptide-loaded polymethylmethacrylate prevents in vivo Staphylococcus aureus biofilm formation. Antimicrob Agents Chemother 51:2594–2596PubMedCrossRefGoogle Scholar
  3. 3.
    Balaban N, Novick RP (1995b) Autocrine regulation of toxin synthesis by Staphylococcus aureus. Proc Natl Acad Sci USA 92:1619–1623PubMedCrossRefGoogle Scholar
  4. 4.
    Balaban N, Goldkorn T, Nhan RT, Dang LB, Scott S, Ridgley RM, Rasooly A, Wright SC, Larrick JW, Rasooly R, Carlson JR (1998) Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus. Science 280:438–440PubMedCrossRefGoogle Scholar
  5. 5.
    Balaban N, Collins LV, Cullor JS, Hume EB, Medina-Acosta E, Vieira-da-Motta O, O'Callaghan R, Rossitto PV, Shirtliff ME, Serafim da Silveira L, Tarkowski A, Torres JV (2000) Prevention of diseases caused by Staphylococcus aureus using the peptide RIP. Peptides 21:1301–1311PubMedCrossRefGoogle Scholar
  6. 6.
    Balaban N, Goldkorn T, Gov Y, Hirshberg M, Koyfman N, Matthews HR, Nhan RT, Singh B, Uziel O (2001) Regulation of Staphylococcus aureus pathogenesis via target of RNAIII- activating protein (TRAP). J Biol Chem 276:2658–2667PubMedGoogle Scholar
  7. 7.
    Balaban N, Giacometti A, Cirioni O, Gov Y, Ghiselli R, Mocchegiani F, Viticchi C, Del Prete MS, Saba V, Scalise G, Dell'Acqua G (2003a) Use of the quorum-sensing inhibitor RNAIII-inhibiting peptide to prevent biofilm formation in vivo by drug-resistant Staphylococcus epidermidis. J Infect Dis 187:625–630PubMedCrossRefGoogle Scholar
  8. 8.
    Balaban N, Gov Y, Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, Orlando F, D'Amato G, Saba V, Scalise G, Bernes S, Mor A (2004) A chimeric peptide composed of a dermaseptin derivative and an RNA III-inhibiting peptide prevents graft-associated infections by antibiotic-resistant staphylococci. Antimicrob Agents Chemother 48:2544–2550PubMedCrossRefGoogle Scholar
  9. 9.
    Balaban N, Stoodley P, Fux CA, Wilson S, Costerton JW, Dell'Acqua G (2005) Prevention of staphylococcal biofilm-associated infections by the quorum sensing inhibitor RIP. Clin Orthop Relat Res 437:48–54PubMedCrossRefGoogle Scholar
  10. 10.
    Balaban N, Cirioni O, Giacometti A, Ghiselli R, Braunstein J, Silvestri C, Mocchegiani F, Saba V, Scalise G (2007) Treatment of Staphylococcus aureus biofilm infection by the quorum sensing inhibitor RIP. Antimicrob Agents Chemother 51:2226–2229PubMedCrossRefGoogle Scholar
  11. 11.
    Bjarnsholt T, Jensen PO, Rasmussen TB, Christophersen L, Calum H, Hentzer M, Hougen HP, Rygaard J, Moser C, Eberl L, Hoiby N, Givskov M (2005b) Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology 151:3873–3880PubMedCrossRefGoogle Scholar
  12. 12.
    Cirioni O, Giacometti A, Ghiselli R, Dell'Acqua G, Gov Y, Kamysz W, Lukasiak J, Mocchegiani F, Orlando F, D'Amato G, Balaban N, Saba V, Scalise G (2003) Prophylactic efficacy of topical temporin A and RNAIII-inhibiting peptide in a subcutaneous rat Pouch model of graft infection attributable to staphylococci with intermediate resistance to glycopeptides. Circulation 108:767–771PubMedCrossRefGoogle Scholar
  13. 13.
    Cirioni O, Giacometti A, Ghiselli R, Dell'acqua G, Orlando F, Mocchegiani F, Silvestri C, Licci A, Saba V, Scalise G, Balaban N (2006) RNAIII-inhibiting peptide significantly reduces bacterial load and enhances the effect of antibiotics in the treatment of central venous catheter-associated Staphylococcus aureus infections. J Infect Dis 193:180–186PubMedCrossRefGoogle Scholar
  14. 14.
    Dell'Acqua G, Giacometti A, Cirioni O, Ghiselli R, Saba V, Scalise G, Gov Y, Balaban N (2004) Suppression of drug-resistant staphylococcal infections by the quorum-sensing inhibitor RNAIII-inhibiting peptide. J Infect Dis 190:318–320PubMedCrossRefGoogle Scholar
  15. 15.
    Domenico P, Gurzenda E, Giacometti A, Cirioni O, Ghiselli R, Orlando F, Korem M, Saba V, Scalise G, Balaban N (2004) BisEDT and RIP act in synergy to prevent graft infections by resistant staphylococci. Peptides 25:2047–2053PubMedCrossRefGoogle Scholar
  16. 16.
    Giacometti A, Cirioni O, Gov Y, Ghiselli R, Del Prete DS, Mocchegiani F, Saba V, Orlando F, Scalise G, Balaban N, Dell'Acqua G (2003) RNAIII inhibiting peptide (RIP) inhibits in vivo biofilm formation of drug-resistant Staphylococcus aureus. Antimicrob Agents Chemother 47:1979–1983PubMedCrossRefGoogle Scholar
  17. 17.
    Giacometti A, Cirioni O, Ghiselli R, Dell'Acqua G, Orlando F, D'Amato G, Mocchegiani F, Silvestri C, Del Prete MS, Rocchi M, Balaban N, Saba V, Scalise G (2005) RNAIII-inhibiting peptide improves efficacy of clinically used antibiotics in a murine model of staphylococcal sepsis. Peptides 26:169–175PubMedCrossRefGoogle Scholar
  18. 18.
    Gov Y, Bitler A, Dell'Acqua G, Torres JV, Balaban N (2001) RNAIII inhibiting peptide (RIP), a global inhibitor of Staphylococcus aureus: structure and function analysis. Peptides 22:1609–1620PubMedCrossRefGoogle Scholar
  19. 19.
    Gov Y, Borovok I, Korem M, Singh VK, Jayaswal RK, Wilkinson BJ, Rich SM, Balaban N (2004) Quorum sensing in Staphylococci is regulated via phosphorylation of three conserved histidine residues. J Biol Chem 279:14665–14672PubMedCrossRefGoogle Scholar
  20. 20.
    Hentzer M, Givskov M (2003) Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J Clin Invest 112:1300–1307PubMedGoogle Scholar
  21. 21.
    Hentzer M, Riedel K, Rasmussen TB, Heydorn A, Andersen JB, Parsek MR, Rice SA, Eberl L, Molin S, Hoiby N, Kjelleberg S, Givskov M (2002) Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 148:87–102PubMedGoogle Scholar
  22. 22.
    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, Høiby N, Givskov M (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22:3803–3815PubMedCrossRefGoogle Scholar
  23. 23.
    Ji G, Beavis R, Novick RP (1997) Bacterial interference caused by autoinducing peptide variants. Science 276:2027–2030PubMedCrossRefGoogle Scholar
  24. 24.
    Korem M, Sheoran A, Gov Y, Borovok I, Tzipori S, Balaban N (2003) Characterization of RAP, a quorum sensing activator in Staphylococccus aureus. FEMS Microbiol Lett 223:167–175PubMedCrossRefGoogle Scholar
  25. 25.
    Korem M, Gov Y, Kiran MD, Balaban N (2005) Transcriptional profiling of target of RNAIII-activating protein, a master regulator of staphylococcal virulence. Infect Immun 73:6220–6228PubMedCrossRefGoogle Scholar
  26. 26.
    Lyon GJ, Mayville P, Muir TW, Novick RP (2000) Rational design of a global inhibitor of the virulence response in Staphylococcus aureus, based in part on localization of the site of inhibition to the receptor-histidine kinase, AgrC. Proc Natl Acad Sci USA 97:13330–13335PubMedCrossRefGoogle Scholar
  27. 27.
    Manefield M, Harris L, Rice SA, de Nys R, Kjelleberg S (2000) Inhibition of luminescence and virulence in the black tiger prawn (Penaeus monodon) pathogen Vibrio harveyi by intercellular signal antagonists. Appl Environ Microbiol 66:2079–2084PubMedCrossRefGoogle Scholar
  28. 28.
    Mayville P, Ji G, Beavis R, Yang H, Goger M, Novick RP, Muir TW (1999) Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc Natl Acad Sci USA 96:1218–1223PubMedCrossRefGoogle Scholar
  29. 29.
    Qiu R, Pei W, Zhang L, Lin J, Ji G (2005) Identification of the putative staphylococcal AgrB catalytic residues involving the proteolytic cleavage of AgrD to generate autoinducing peptide. J Biol Chem 280:16695–16704PubMedCrossRefGoogle Scholar
  30. 30.
    Rasmussen TB, Bjarnsholt T, Skindersoe ME, Hentzer M, Kristoffersen P, Kote M, Nielsen J, Eberl L, Givskov M (2005a) Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol 187:1799–1814PubMedCrossRefGoogle Scholar
  31. 31.
    Rasmussen TB, Skindersoe ME, Bjarnsholt T, Phipps RK, Christensen KB, Jensen PO, Andersen JB, Koch B, Larsen TO, Hentzer M, Eberl L, Hoiby N, Givskov M (2005b) Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 151:1325–1340PubMedCrossRefGoogle Scholar
  32. 32.
    Vieira-da-Motta O, Damasceno Ribeiro P, Dias da Silva W, Medina-Acosta E (2001) RNAIII inhibiting peptide (RIP) inhibits agr-regulated toxin production. Peptides 22:1621–1627PubMedCrossRefGoogle Scholar
  33. 33.
    Wright JS III, Jin R, Novick RP (2005) Transient interference with staphylococcal quorum sensing blocks abscess formation. Proc Natl Acad Sci USA 102:1691–1696PubMedCrossRefGoogle Scholar
  34. 34.
    Yang G, Cheng H, Liu C, Xue Y, Gao Y, Liu N, Gao B, Wang D, Li S, Shen B, Shao N (2003) Inhibition of Staphylococcus aureus pathogenesis in vitro and in vivo by RAP-binding peptides. Peptides 24:1823–1828PubMedCrossRefGoogle Scholar
  35. 35.
    Yang G, Gao Y, Dong J, Liu C, Xue Y, Fan M, Shen B, Shao N (2005) A novel peptide screened by phage display can mimic TRAP antigen epitope against Staphylococcus aureus infections. J Biol Chem 280:27431–27435PubMedCrossRefGoogle Scholar
  36. 36.
    Yang G, Gao Y, Dong J, Xue Y, Fan M, Shen B, Liu C, Shao N (2006) A novel peptide isolated from phage library to substitute a complex system for a vaccine against staphylococci infection. Vaccine 24:1117–1123PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Cummings School of Veterinary Medicine, Department of Biomedical SciencesTufts UniversityNorth GraftonUSA
  2. 2.BioCentrum-DTUTechnical University of DenmarkKgs LyngbyDenmark
  3. 3.Innovation, Cultures & Enzymes DivisionChristian Hansen A/SHørsholmDenmark

Personalised recommendations