• A Corrigendum to this article was published on 14 September 2016

Abstract

The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.

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Acknowledgements

We thank V. Winstel for technical assistance and A. Bobic, S. Heilbronner, W. Hoffmann, A. Jorge, D. Kretschmer, A. Kulik, M. Nega, E. Stegmann, V. Winstel, T. Weber, and W. Wohlleben for assistance and helpful discussions. Thanks to Bruker Daltonics for selected initial high-resolution mass spectrometry analysis and to T. Paululat for NMR experiments. This work was financed by German Research Council grants GRK1708 to S.G. and A.P.; TRR156, Schi510/8-1, and PE805/5-1 to B.S. and A.P.; TRR34 to C.W. and A.P; and SFB766 to C.W., H.B.-O., S.G., and A.P.; and by the German Center for Infection Research (DZIF) to C.W., A.P., B.K., M.W., and H.B.-O.

Author information

Author notes

    • Daniela Janek

    Present address: Boehringer Ingelheim, 88400 Biberach, Germany.

    • Alexander Zipperer
    •  & Martin C. Konnerth

    These authors contributed equally to this work.

Affiliations

  1. Interfaculty Institute of Microbiology and Infection Medicine, Infection Biology, University of Tübingen, 72076 Tübingen, Germany

    • Alexander Zipperer
    • , Claudia Laux
    • , Daniela Janek
    • , Christoph Slavetinsky
    • , Andreas Peschel
    •  & Bernhard Krismer
  2. German Centre for Infection Research (DZIF), Partner Site Tübingen, 72076 Tübingen, Germany

    • Alexander Zipperer
    • , Claudia Laux
    • , Daniela Janek
    • , Christopher Weidenmaier
    • , Christoph Slavetinsky
    • , Matthias Willmann
    • , Heike Brötz-Oesterhelt
    • , Andreas Peschel
    •  & Bernhard Krismer
  3. Institute of Organic Chemistry, University of Tübingen, 72076 Tübingen, Germany

    • Martin C. Konnerth
    • , Nadine A. Schilling
    •  & Stephanie Grond
  4. Interfaculty Institute of Microbiology and Infection Medicine, Microbial Bioactive Compounds, University of Tübingen, 72076 Tübingen, Germany

    • Anne Berscheid
    •  & Heike Brötz-Oesterhelt
  5. Interfaculty Institute of Microbiology and Infection Medicine, Medical Microbiology, University of Tübingen, 72076 Tübingen, Germany

    • Christopher Weidenmaier
    • , Matthias Marschal
    •  & Matthias Willmann
  6. Department of Dermatology, Division of Dermatooncology, University of Tübingen, 72076 Tübingen, Germany

    • Marc Burian
    •  & Birgit Schittek
  7. Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany

    • Nadine A. Schilling
    •  & Hubert Kalbacher

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Contributions

A.Z. isolated lugdunin, designed experiments and investigated the biological activities of lugdunin. M.C.K. purified lugdunin, designed experiments and determined the structure of lugdunin. D.J. identified IVK28 and performed transposon mutagenesis. A.B. designed and performed precursor incorporation studies. C.L. designed the human colonization study and analysed data. M.B., A.Z., C.S. and C.W. performed animal experiments, and M.W. and C.W. analysed data and performed statistical analysis. M.M. provided patient samples and supported MALDI-TOF analysis. N.A.S. and H.K. established total chemical synthesis of lugdunin. B.K. isolated lugdunin, analysed operon structure and performed bioinformatic analyses, A.Z., M.C.K., B.S., H.B.-O., S.G., A.P. and B.K. designed the study, analysed results, and wrote the paper.

Competing interests

Tuebingen University has filed a provisional patent application that covers the compound lugdunin and derivatives thereof, as well as the application of lugdunin- producing bacteria for the prevention of bacterial infections (European patent application number EP 15 160 285.1).

Corresponding author

Correspondence to Andreas Peschel.

Reviewer Information Nature thanks G. Challis, M. Gilmore and K. Lewis for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature18634

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