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Essential Staphylococcus aureus toxin export system

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.

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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.

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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.

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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.

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Correspondence to Michael Otto.

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The authors declare no competing financial interests.

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

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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

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