Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Essential Staphylococcus aureus toxin export system

Nature Medicine volume 19, pages 364–367 (2013)Cite this article

Subjects

Abstract

Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus1 calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection2. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis3,4,5 and have a major impact on the ability of highly virulent S. aureus to cause disease3,6. However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Pmt PSM exporter.
Figure 2: Absence of Pmt leads to intracellular accumulation of PSMs and major cellular defects.
Figure 3: Pmt contributes to producer immunity and defense against PSM-based bacterial interference.
Figure 4: Pmt promotes virulence phenotypes and the progression of S. aureus skin infection.

Similar content being viewed by others

References

  1. Lowy, F.D. Antimicrobial resistance: the example of Staphylococcus aureus. J. Clin. Invest. 111, 1265–1273 (2003).

    Article  CAS  Google Scholar 

  2. Alksne, L.E. & Projan, S.J. Bacterial virulence as a target for antimicrobial chemotherapy. Curr. Opin. Biotechnol. 11, 625–636 (2000).

    Article  CAS  Google Scholar 

  3. Wang, R. et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat. Med. 13, 1510–1514 (2007).

    Article  CAS  Google Scholar 

  4. Wang, R. et al. Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm-associated infection in mice. J. Clin. Invest. 121, 238–248 (2011).

    Article  CAS  Google Scholar 

  5. Kretschmer, D. et al. Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus. Cell Host Microbe 7, 463–473 (2010).

    Article  CAS  Google Scholar 

  6. Kobayashi, S.D. et al. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection. J. Infect. Dis. 204, 937–941 (2011).

    Article  CAS  Google Scholar 

  7. Cheung, G.Y. et al. Staphylococcus epidermidis strategies to avoid killing by human neutrophils. PLoS Pathog. 6, e1001133 (2010).

    Article  Google Scholar 

  8. Cheung, G.Y., Duong, A.C. & Otto, M. Direct and synergistic hemolysis caused by Staphylococcus phenol-soluble modulins: implications for diagnosis and pathogenesis. Microbes Infect. 14, 380–386 (2012).

    Article  CAS  Google Scholar 

  9. Periasamy, S. et al. How Staphylococcus aureus biofilms develop their characteristic structure. Proc. Natl. Acad. Sci. USA 109, 1281–1286 (2012).

    Article  CAS  Google Scholar 

  10. Schwartz, K., Syed, A.K., Stephenson, R.E., Rickard, A.H. & Boles, B.R. Functional amyloids composed of phenol soluble modulins stabilize Staphylococcus aureus biofilms. PLoS Pathog. 8, e1002744 (2012).

    Article  CAS  Google Scholar 

  11. Rautenberg, M., Joo, H.S., Otto, M. & Peschel, A. Neutrophil responses to staphylococcal pathogens and commensals via the formyl peptide receptor 2 relates to phenol-soluble modulin release and virulence. FASEB J. 25, 1254–1263 (2011).

    Article  CAS  Google Scholar 

  12. Peterson, M.M. et al. Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureus infection. Cell Host Microbe 4, 555–566 (2008).

    Article  CAS  Google Scholar 

  13. Rothfork, J.M. et al. Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: new role for the NADPH oxidase in host defense. Proc. Natl. Acad. Sci. USA 101, 13867–13872 (2004).

    Article  CAS  Google Scholar 

  14. Surewaard, B.G. et al. Inactivation of staphylococcal phenol soluble modulins by serum lipoprotein particles. PLoS Pathog. 8, e1002606 (2012).

    Article  CAS  Google Scholar 

  15. Forsman, H., Christenson, K., Bylund, J. & Dahlgren, C. Receptor-dependent and -independent immunomodulatory effects of phenol-soluble modulin peptides from Staphylococcus aureus on human neutrophils are abrogated through peptide inactivation by reactive oxygen species. Infect. Immun. 80, 1987–1995 (2012).

    Article  CAS  Google Scholar 

  16. Mehlin, C., Headley, C.M. & Klebanoff, S.J. An inflammatory polypeptide complex from Staphylococcus epidermidis: isolation and characterization. J. Exp. Med. 189, 907–918 (1999).

    Article  CAS  Google Scholar 

  17. Vuong, C. et al. Regulated expression of pathogen-associated molecular pattern molecules in Staphylococcus epidermidis: quorum-sensing determines pro-inflammatory capacity and production of phenol-soluble modulins. Cell Microbiol. 6, 753–759 (2004).

    Article  CAS  Google Scholar 

  18. Yao, Y., Sturdevant, D.E. & Otto, M. Genomewide analysis of gene expression in Staphylococcus epidermidis biofilms: insights into the pathophysiology of S. epidermidis biofilms and the role of phenol-soluble modulins in formation of biofilms. J. Infect. Dis. 191, 289–298 (2005).

    Article  CAS  Google Scholar 

  19. Queck, S.Y. et al. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol. Cell 32, 150–158 (2008).

    Article  CAS  Google Scholar 

  20. Cheung, G.Y., Wang, R., Khan, B.A., Sturdevant, D.E. & Otto, M. Role of the accessory gene regulator agr in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. Infect. Immun. 79, 1927–1935 (2011).

    Article  CAS  Google Scholar 

  21. Otto, M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu. Rev. Microbiol. 64, 143–162 (2010).

    Article  CAS  Google Scholar 

  22. Zolnerciks, J.K., Andress, E.J., Nicolaou, M. & Linton, K.J. Structure of ABC transporters. Essays Biochem. 50, 43–61 (2011).

    Article  CAS  Google Scholar 

  23. Walker, J.E., Saraste, M., Runswick, M.J. & Gay, N.J. Distantly related sequences in the α- and β-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1, 945–951 (1982).

    Article  CAS  Google Scholar 

  24. Otto, M. Staphylococcus epidermidis—the 'accidental' pathogen. Nat. Rev. Microbiol. 7, 555–567 (2009).

    Article  CAS  Google Scholar 

  25. Cogen, A.L. et al. Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. J. Invest. Dermatol. 130, 192–200 (2010).

    Article  CAS  Google Scholar 

  26. Joo, H.S., Cheung, G.Y. & Otto, M. Antimicrobial activity of community-associated methicillin-resistant Staphylococcus aureus is caused by phenol-soluble modulin derivatives. J. Biol. Chem. 286, 8933–8940 (2011).

    Article  CAS  Google Scholar 

  27. Malachowa, N. et al. Global changes in Staphylococcus aureus gene expression in human blood. PLoS ONE 6, e18617 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Dorschner, R.A. et al. The mammalian ionic environment dictates microbial susceptibility to antimicrobial defense peptides. FASEB J. 20, 35–42 (2006).

    Article  CAS  Google Scholar 

  30. Wells, J.M., Wilson, P.W. & Le Page, R.W. Improved cloning vectors and transformation procedure for Lactococcus lactis. J. Appl. Bacteriol. 74, 629–636 (1993).

    Article  CAS  Google Scholar 

  31. Augustin, J. & Gotz, F. Transformation of Staphylococcus epidermidis and other staphylococcal species with plasmid DNA by electroporation. FEMS Microbiol. Lett. 54, 203–207 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Vandecasteele, S.J., Peetermans, W.E., Merckx, R., Van Ranst, M. & Van Eldere, J. Use of gDNA as internal standard for gene expression in staphylococci in vitro and in vivo. Biochem. Biophys. Res. Commun. 291, 528–534 (2002).

    Article  CAS  Google Scholar 

  34. Li, M. et al. The antimicrobial peptide-sensing system aps of Staphylococcus aureus. Mol. Microbiol. 66, 1136–1147 (2007).

    Article  CAS  Google Scholar 

  35. Li, M. et al. Gram-positive three-component antimicrobial peptide-sensing system. Proc. Natl. Acad. Sci. USA 104, 9469–9474 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH) (grant ZIA AI000904-10) to M.O. and the National Natural Science Foundation of China (grants 30900026, 81171623 and 81261120387) to M.L. We thank J. Kok (University of Groningen), F. Lowy (Columbia University) and G. Dunny (University of Minnesota) for lactococcal strains and plasmids and A. Peschel for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Som S Chatterjee, Hwang-Soo Joo, Anthony C Duong, Thomas D Dieringer, Vee Y Tan, Gordon Y C Cheung & Michael Otto

  2. Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Yan Song & Min Li

  3. Microscopy Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA

    Elizabeth R Fischer

Authors
  1. Som S Chatterjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hwang-Soo Joo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anthony C Duong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas D Dieringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vee Y Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elizabeth R Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gordon Y C Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.-S.J. and M.O. performed HPLC measurements for PSM detection. E.R.F. performed electron microscopy. S.S.C., G.Y.C.C., A.C.D., V.Y.T. and T.D.D. performed mouse experiments. Y.S. and M.L. designed and performed experiments with neutrophils and human blood. S.S.C. performed all other experiments. S.S.C. and M.O. analyzed data, designed the study and wrote the paper.

Corresponding author

Correspondence to Michael Otto.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1–3 (PDF 3366 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chatterjee, S., Joo, HS., Duong, A. et al. Essential Staphylococcus aureus toxin export system. Nat Med 19, 364–367 (2013). https://doi.org/10.1038/nm.3047

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3047

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research