Development of Quorum-Sensing Inhibitors Targeting the fsr System of Enterococcus faecalis

  • Ravindra Pal Singh
  • Jiro Nakayama


Enterococcus spp. can cause illnesses such as bacteremia, endocarditis, urinary tract infections, posttreatment endophthalmitis, and endodontic infections (Murray 2000; Marothi et al. 2005). Medical treatment of these infectious diseases depends largely on bactericidal or bacteriostatic antibiotics. However, frequent use of such antibiotics has led to the development of drug-resistant bacterial strains, which are difficult to treat (Marothi et al. 2005; Murray 2000). As a result, the blockage of bacterial quorum-sensing (QS) systems has attracted attention owing to its potential to attenuate bacterial virulence without inducing bactericidal pressures that lead to drug resistance. This approach, called quorum quenching (QQ), can be undertaken partially or completely independently of antibiotic treatment. Among several QQ strategies, the use of QS inhibitors (QSIs), which are small molecules that have no adverse effects on bacteria, offers advantages in terms of drug delivery and decreased damage to commensal microbiota.


Green Fluorescent Protein Quorum Quenching Commensal Microbiota Endodontic Infection Actinomycete Culture 
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.



This research was supported in part by Grants-in-Aid for Scientific Research (B) No. 24380050 and Grant-in-Aid for JSPS Fellows No. 25-03389.


  1. Chen KJ, Lai CC, Sun MH, Chen TL, Yang KJ, Kuo YH, Chao AN, Wu WC (2009) Postcataract endophthalmitis caused by Enterococcus faecalis. Ocul Immunol Inflamm 17:364–369PubMedCrossRefGoogle Scholar
  2. Chuang ON, Schlievert PM, Wells CL, Manias DA, Tripp TJ, Dunny GM (2009) Multiple functional domains of Enterococcus faecalis aggregation substance Asc10 contribute to endocarditis virulence. Infect Immun 77:539–548PubMedCrossRefPubMedCentralGoogle Scholar
  3. Chuang-Smith O, Wells C, Henry-Stanley M, Dunny GM (2010) Acceleration of Enterococcus faecalis biofilm formation by aggregation substance expression in an ex vivo model of cardiac valve colonization. PLoS One 5:e15798PubMedCrossRefPubMedCentralGoogle Scholar
  4. Desouky SE, Nishiguchi K, Zendo T, Igarashi Y, Williams P, Sonomoto K, Nakayama J (2013) High-throughput screening of inhibitors targeting Agr/Fsr quorum sensing in Staphylococcus aureus and Enterococcus faecalis. Biosci Biotechnol Biochem 77:923–927PubMedCrossRefGoogle Scholar
  5. Engelbert M, Mylonakis E, Ausubel FM, Calderwood SB, Gilmore MS (2004) Contribution of gelatinase, serine protease, and fsr to the pathogenesis of Enterococcus faecalis endophthalmitis. Infect Immun 72:3628–3633PubMedCrossRefPubMedCentralGoogle Scholar
  6. Hirt H, Erlandsen SL, Dunny GM (2000) Heterologous inducible expression of Enterococcus faecalis pCF10 aggregation substance Asc10 in Lactococcus lactis and Streptococcus gordonii contributes to cell hydrophobicity and adhesion to fibrin. J Bacteriol 182:2299–2306PubMedCrossRefPubMedCentralGoogle Scholar
  7. Ji G, Beavis R, Novick RP (1997) Bacterial interference caused by autoinducing peptide variants. Science 276:2027–2030PubMedCrossRefGoogle Scholar
  8. Khalessi AM, Pack AR, Thomson WM, Tompkins GR (2004) An in vivo study of the plaque control efficacy of Persica: a commercially available herbal mouthwash containing extracts of Salvadora persica. Int Dent J 54:279–283PubMedCrossRefGoogle Scholar
  9. Ma P, Nishiguchi K, Yuille HM, Davis LM, Nakayama J, Phillips-Jones MK (2011) Anti-HIV siamycin I directly inhibits autophosphorylation activity of the bacterial FsrC quorum sensor and other ATP-dependent enzyme activities. FEBS Lett 585:2660–2664PubMedCrossRefGoogle Scholar
  10. Marothi YA, Agnihotri H, Dubey D (2005) Enterococcal resistance- an overview. Indian J Med Microbiol 23:214–219PubMedGoogle Scholar
  11. Murray BE (2000) Vancomycin-resistant enterococcal infections. N Engl J Med 342:710–721PubMedCrossRefGoogle Scholar
  12. Mylonakis E, Engelbert M, Qin X, Sifri CD, Murray BE, Ausubel FM, Gilmore MS, Calderwood SB (2002) The Enterococcus faecalis fsrB gene, a key component of the fsr quorum sensing system, is associated with virulence in the rabbit endophthalmitis model. Infect Immun 70:4678–4681PubMedCrossRefPubMedCentralGoogle Scholar
  13. Nakayama J, Cao Y, Horii T, Sakuda S, Akkermans AD, de Vos WM, Nagasawa H (2001) Gelatinase biosynthesis activating pheromone: a peptide lactone that mediates a quorum sensing in Enterococcus faecalis. Mol Microbiol 41:145–154PubMedCrossRefGoogle Scholar
  14. Nakayama J, Tanaka E, Kariyama R, Nagata K, Nishiguchi K, Mitsuhata R, Uemura Y, Tanokura M, Kumon H, Sonomoto K (2007) Siamycin attenuates fsr quorum sensing mediated by a gelatinase biosynthesis-activating pheromone in Enterococcus faecalis. J Bacteriol 189:1358–1365PubMedCrossRefPubMedCentralGoogle Scholar
  15. Nakayama J, Uemura Y, Nishiguchi K, Yoshimura N, Igarashi Y, Sonomoto K (2009) Ambuic acid inhibits the biosynthesis of cyclic peptide quormones in gram-positive bacteria. Antimicrob Agents Chemother 53:580–586PubMedCrossRefPubMedCentralGoogle Scholar
  16. Nakayama J, Yokohata R, Sato M, Suzuki T, Matsufuji T, Nishiguchi K, Kawai T, Yamanaka Y, Nagata K, Tanokura M, Sonomoto K (2013) Development of a peptide antagonist against fsr quorum sensing of Enterococcus faecalis. ACS Chem Biol 8:804–811PubMedCrossRefGoogle Scholar
  17. Nishiguchi K, Nagata K, Tanokura M, Sonomoto K, Nakayama J (2009) Structure-activity relationship of gelatinase biosynthesis-activating pheromone of Enterococcus faecalis. J Bacteriol 191:641–650PubMedCrossRefPubMedCentralGoogle Scholar
  18. Otto M, Submuth R, Vuong C, Jung G, Götz F (1999) Inhibition of virulence factor expression in Staphylococcus aureus by the Staphylococcus epidermidis agr pheromone and derivatives. FEBS Lett 450:257–262PubMedCrossRefGoogle Scholar
  19. Phillips-Jones MK, Patching SG, Edara S, Nakayama J, Hussain R, Siligardi G (2013) Interactions of the intact FsrC membrane histidine kinase with the tricyclic peptide inhibitor siamycin I revealed through synchrotron radiation circular dichroism. Phys Chem Chem Phys 15:444–447PubMedCrossRefGoogle Scholar
  20. Rezaei A, Oyong GG, Borja VB, Inoue M, Abe T, Tamamura R, Nagatsuka H, Setsu K, Buery RR (2011) Molecular screening of anti-quorum sensing capability of Salvadora persica on Enterococcus faecalis. J Hard Tissue Biol 20:115–124CrossRefGoogle Scholar
  21. Scott IU, Loo RH, Flynn HW Jr, Miller D (2003) Endophthalmitis caused by Enterococcus faecalis: antibiotic selection and treatment outcomes. Ophthalmology 110:1573–1577PubMedCrossRefGoogle Scholar
  22. Shojima A, Nakayama J (2014) Quorum sensing in gram positive bacteria: assay protocols for staphylococcal agr and enterococcal fsr systems. In: Donelli G (ed) Microbial biofilms: methods and protocols, vol 1147. Springer, Dordrecht, pp 33–41CrossRefGoogle Scholar
  23. Suzuki T, Wada T, Kozai S, Ike Y, Gilmore MS, Ohashi Y (2008) Contribution of secreted proteases to the pathogenesis of postoperative Enterococcus faecalis endophthalmitis. J Cataract Refract Surg 34:1776–1784PubMedCrossRefGoogle Scholar
  24. Tal-Gan Y, Stacy DM, Foegen MK, Koenig DW, Blackwell HE (2013) Highly potent inhibitors of quorum sensing in Staphylococcus aureus revealed through a systematic synthetic study of the group-III autoinducing peptide. J Am Chem Soc 135:7869–7882PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2015

Authors and Affiliations

  1. 1.Laboratory of Microbial Technology, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate SchoolKyushu UniversityFukuokaJapan

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