Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization


Commensal bacteria are known to inhibit pathogen colonization; however, complex host–microbe and microbe–microbe interactions have made it difficult to gain a detailed understanding of the mechanisms involved in the inhibition of colonization1. Here we show that the serine protease Esp2,3 secreted by a subset of Staphylococcus epidermidis, a commensal bacterium, inhibits biofilm formation and nasal colonization by Staphylococcus aureus, a human pathogen4. Epidemiological studies have demonstrated that the presence of Esp-secreting S. epidermidis in the nasal cavities of human volunteers correlates with the absence of S. aureus. Purified Esp inhibits biofilm formation and destroys pre-existing S. aureus biofilms. Furthermore, Esp enhances the susceptibility of S. aureus in biofilms to immune system components. In vivo studies have shown that Esp-secreting S. epidermidis eliminates S. aureus nasal colonization. These findings indicate that Esp hinders S. aureus colonization in vivo through a novel mechanism of bacterial interference, which could lead to the development of novel therapeutics to prevent S. aureus colonization and infection.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Inhibition of S. aureus biofilm formation and destruction of S. aureus biofilms by S. epidermidis.
Figure 2: Isolation and characterization of the serine protease Esp, the factor responsible for the biofilm-destruction activity, secreted by inhibitory S. epidermidis.
Figure 3: Elimination effect of inhibitory S. epidermidis cells on S. aureus nasal colonization.


  1. 1

    Wertheim, H. F. et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect. Dis. 5, 751–762 (2005)

    Article  Google Scholar 

  2. 2

    Moon, J. L., Banbula, A., Oleksy, A., Mayo, J. A. & Travis, J. Isolation and characterization of a highly specific serine endopeptidase from an oral strain of Staphylococcus epidermidis . Biol. Chem. 382, 1095–1099 (2001)

    CAS  Article  Google Scholar 

  3. 3

    Dubin, G. et al. Molecular cloning and biochemical characterisation of proteases from Staphylococcus epidermidis . Biol. Chem. 382, 1575–1582 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Lowy, F. D. Staphylococcus aureus infections. N. Engl. J. Med. 339, 520–532 (1998)

    CAS  Article  Google Scholar 

  5. 5

    Klein, E., Smith, D. L. & Laxminarayan, R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg. Infect. Dis. 13, 1840–1846 (2007)

    Article  Google Scholar 

  6. 6

    Srinivasan, A., Dick, J. D. & Perl, T. M. Vancomycin resistance in staphylococci. Clin. Microbiol. Rev. 15, 430–438 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Kluytmans, J., van Belkum, A. & Verbrugh, H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin. Microbiol. Rev. 10, 505–520 (1997)

    CAS  Article  Google Scholar 

  8. 8

    Peacock, S. J., de Silva, I. & Lowy, F. D. What determines nasal carriage of Staphylococcus aureus? Trends Microbiol. 9, 605–610 (2001)

    CAS  Article  Google Scholar 

  9. 9

    Graham, P. L., Lin, S. X. & Larson, E. L. A U.S. population-based survey of Staphylococcus aureus colonization. Ann. Intern. Med. 144, 318–325 (2006)

    Article  Google Scholar 

  10. 10

    Kuehnert, M. J. et al. Prevalence of Staphylococcus aureus nasal colonization in the United States, 2001–2002. J. Infect. Dis. 193, 172–179 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Shopsin, B. et al. Prevalence of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in the community. J. Infect. Dis. 182, 359–362 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Perl, T. M. et al. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N. Engl. J. Med. 346, 1871–1877 (2002)

    CAS  Article  Google Scholar 

  13. 13

    von Eiff, C., Becker, K., Machka, K., Stammer, H. & Peters, G. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N. Engl. J. Med. 344, 11–16 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Lehrer, R. I. Primate defensins. Nature Rev. Microbiol. 2, 727–738 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Otto, M. Staphylococcus aureus and Staphylococcus epidermidis peptide pheromones produced by the accessory gene regulator agr system. Peptides 22, 1603–1608 (2001)

    CAS  Article  Google Scholar 

  16. 16

    Mackowiak, P. A. The normal microbial flora. N. Engl. J. Med. 307, 83–93 (1982)

    CAS  Article  Google Scholar 

  17. 17

    Brook, I. Bacterial interference. Crit. Rev. Microbiol. 25, 155–172 (1999)

    CAS  Article  Google Scholar 

  18. 18

    Falagas, M. E., Rafailidis, P. I. & Makris, G. C. Bacterial interference for the prevention and treatment of infections. Int. J. Antimicrob. Agents 31, 518–522 (2008)

    CAS  Article  Google Scholar 

  19. 19

    Uehara, Y. et al. H2O2 produced by viridans group streptococci may contribute to inhibition of methicillin-resistant Staphylococcus aureus colonization of oral cavities in newborns. Clin. Infect. Dis. 32, 1408–1413 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Speck, W. T., Driscoll, J. M., Polin, R. A. & Rosenkranz, H. S. Effect of bacterial flora on staphylococcal colonisation of the newborn. J. Clin. Pathol. 31, 153–155 (1978)

    CAS  Article  Google Scholar 

  21. 21

    Poutrel, B. & Lerondelle, C. Protective effect in the lactating bovine mammary gland induced by coagulase-negative staphylococci against experimental Staphylococcus aureus infections. Ann. Rech. Vet. 11, 327–332 (1980)

    CAS  PubMed  Google Scholar 

  22. 22

    Lina, G. et al. Bacterial competition for human nasal cavity colonization: role of staphylococcal agr alleles. Appl. Environ. Microbiol. 69, 18–23 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Peacock, S. J. et al. Determinants of acquisition and carriage of Staphylococcus aureus in infancy. J. Clin. Microbiol. 41, 5718–5725 (2003)

    Article  Google Scholar 

  24. 24

    Nicoll, T. R. & Jensen, M. M. Preliminary studies on bacterial interference of staphylococcosis of chickens. Avian Dis. 31, 140–144 (1987)

    CAS  Article  Google Scholar 

  25. 25

    Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Gao, Z., Tseng, C. H., Pei, Z. & Blaser, M. J. Molecular analysis of human forearm superficial skin bacterial biota. Proc. Natl Acad. Sci. USA 104, 2927–2932 (2007)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005)

    ADS  Article  Google Scholar 

  30. 30

    Bik, E. M. et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc. Natl Acad. Sci. USA 103, 732–737 (2006)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Carroll, K. C., Leonard, R. B., Newcomb-Gayman, P. L. & Hillyard, D. R. Rapid detection of the staphylococcal mecA gene from BACTEC blood culture bottles by the polymerase chain reaction. Am. J. Clin. Pathol. 106, 600–605 (1996)

    CAS  Article  Google Scholar 

  32. 32

    Iwase, T., Seki, K., Shinji, H., Mizunoe, Y. & Masuda, S. Development of a real-time PCR assay for the detection and identification of Staphylococcus capitis, Staphylococcus haemolyticus and Staphylococcus warneri . J. Med. Microbiol. 56, 1346–1349 (2007)

    CAS  Article  Google Scholar 

  33. 33

    Iwase, T. et al. Rapid identification and specific quantification of Staphylococcus epidermidis by 5′ nuclease real-time polymerase chain reaction with a minor groove binder probe. Diagn. Microbiol. Infect. Dis. 60, 217–219 (2008)

    CAS  Article  Google Scholar 

  34. 34

    Hiramatsu, K. et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 350, 1670–1673 (1997)

    CAS  Article  Google Scholar 

  35. 35

    Ohara-Nemoto, Y. et al. Characterization and molecular cloning of a glutamyl endopeptidase from Staphylococcus epidermidis . Microb. Pathog. 33, 33–41 (2002)

    CAS  Article  Google Scholar 

  36. 36

    Cui, L., Lian, J. Q., Neoh, H. M., Reyes, E. & Hiramatsu, K. DNA microarray-based identification of genes associated with glycopeptide resistance in Staphylococcus aureus . Antimicrob. Agents Chemother. 49, 3404–3413 (2005)

    CAS  Article  Google Scholar 

  37. 37

    Bae, T. & Schneewind, O. Allelic replacement in Staphylococcus aureus with inducible counter-selection. Plasmid 55, 58–63 (2006)

    CAS  Article  Google Scholar 

  38. 38

    Augustin, J. & Gotz, F. Transformation of Staphylococcus epidermidis and other staphylococcal species with plasmid DNA by electroporation. FEMS Microbiol. Lett. 66, 203–207 (1990)

    CAS  Article  Google Scholar 

  39. 39

    Hanaki, H. et al. Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J. Antimicrob. Chemother. 42, 199–209 (1998)

    CAS  Article  Google Scholar 

  40. 40

    Neoh, H. M. et al. Mutated response regulator graR is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous vancomycin-intermediate resistance to vancomycin-intermediate resistance. Antimicrob. Agents Chemother. 52, 45–53 (2008)

    CAS  Article  Google Scholar 

  41. 41

    Shinji, H. et al. Lipopolysaccharide-induced biphasic inositol 1,4,5-trisphosphate response and tyrosine phosphorylation of 140-kilodalton protein in mouse peritoneal macrophages. J. Immunol. 158, 1370–1376 (1997)

    CAS  PubMed  Google Scholar 

  42. 42

    Vuong, C. et al. Polysaccharide intercellular adhesin (PIA) protects Staphylococcus epidermidis against major components of the human innate immune system. Cell. Microbiol. 6, 269–275 (2004)

    CAS  Article  Google Scholar 

  43. 43

    Midorikawa, K. et al. Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes. Infect. Immun. 71, 3730–3739 (2003)

    CAS  Article  Google Scholar 

  44. 44

    Machin, D. C. M., Fayers, P. & Pinol, A. In Sample Size Tables for Clinical Studies 2nd edn, chap. 3 (Blackwell Science, 1997)

    Google Scholar 

  45. 45

    Machin, D. C. M., Fayers, P. & Pinol, A. In Sample Size Tables for Clinical Studies 2nd edn, chap. 9 (Blackwell Science, 1997)

    Google Scholar 

  46. 46

    Uehara, Y. et al. Bacterial interference among nasal inhabitants: eradication of Staphylococcus aureus from nasal cavities by artificial implantation of Corynebacterium sp. J. Hosp. Infect. 44, 127–133 (2000)

    CAS  Article  Google Scholar 

  47. 47

    Paule, S. M., Pasquariello, A. C., Thomson, R. B., Kaul, K. L. & Peterson, L. R. Real-time PCR can rapidly detect methicillin-susceptible and methicillin-resistant Staphylococcus aureus directly from positive blood culture bottles. Am. J. Clin. Pathol. 124, 404–407 (2005)

    CAS  Article  Google Scholar 

  48. 48

    Ikeda, Y., Ohara-Nemoto, Y., Kimura, S., Ishibashi, K. & Kikuchi, K. PCR-based identification of Staphylococcus epidermidis targeting gseA encoding the glutamic-acid-specific protease. Can. J. Microbiol. 50, 493–498 (2004)

    CAS  Article  Google Scholar 

Download references


We thank K. Hiramatsu and T. Bae for providing materials and M. Sekiguchi, T. Bae, S. N. Wai, B. E. Uhlin, L. Cui, T. Ito, M. Yoneda, M. Urashima and S. Masuda for discussions, critical comments and advice. Thanks also go to S. Kuramoto, K. Seki, F. Sato, S. Hoshina, T. Ohashi, H. Ikeshima-Kataoka, Y. Yoshizawa, M. Murai and M. Kono for their comments on the study, and to J. Fitzpatrick and M. Okazaki for their comments on the manuscript, and to our colleagues for their assistance. Finally, we thank all persons involved in the study. A part of the study was supported by The Jikei University Research Fund and by The Jikei University Graduate Research Fund.

Author information




T.I. and Y.M. designed the research and wrote the manuscript. All authors contributed the experiments; T.I., H.S., A.T., K.T. and Y.M. for in vitro study and epidemiological study, Y.U. and H.S. for in vivo study, T.A. for statistics. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Tadayuki Iwase.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Table 1 and Supplementary Figures 1- 6 with legends. (PDF 976 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Iwase, T., Uehara, Y., Shinji, H. et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465, 346–349 (2010).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.