Article

A new antibiotic kills pathogens without detectable resistance

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Accepted:
Published online:

Abstract

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

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Change history

  • Corrected online 21 January 2015

    Two minor typos were corrected in the main text and Methods.

Accessions

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

The biosynthetic gene cluster for teixobactin has been deposited with GenBank under accession number KP006601.

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Acknowledgements

This work was supported by NIH grant T-RO1 AI085585 to K.L., by NIH grant AI085612 to A.L.S., by the Charles A. King Trust to B.P.C., and by the German Research Foundation (DFG; SCHN1284/1-2) and the German Center for Infection Research (DZIF) to T.S. and I.E. The NRS strains were provided by the Network on Antimicrobial Resistance in Staphylococcus aureus for distribution by BEI Resources, NIAID, NIH. Preclinical Services offered by NIAID are gratefully acknowledged. We thank H. G. Sahl for reading the manuscript and making comments, A. Makriyannis for suggestions, P. Muller, B. Berdy and S. Kaluziak for taxonomy analysis, and M. Josten for performing mass spectrometry analysis.

Author information

Author notes

    • Losee L. Ling
    •  & Tanja Schneider

    These authors contributed equally to this work.

Affiliations

  1. NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA

    • Losee L. Ling
    • , Aaron J. Peoples
    • , Amy L. Spoering
    • , Dallas E. Hughes
    • , Douglas R. Cohen
    • , Cintia R. Felix
    • , K. Ashley Fetterman
    • , William P. Millett
    • , Anthony G. Nitti
    •  & Ashley M. Zullo
  2. Institute of Medical Microbiology, Immunology and Parasitology—Pharmaceutical Microbiology Section, University of Bonn, Bonn 53115, Germany

    • Tanja Schneider
    • , Ina Engels
    •  & Anna Mueller
  3. German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, 53115 Bonn, Germany

    • Tanja Schneider
    • , Ina Engels
    • , Anna Mueller
    •  & Till F. Schäberle
  4. Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, Massachusetts 02115, USA

    • Brian P. Conlon
    • , Chao Chen
    •  & Kim Lewis
  5. Institute for Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany

    • Till F. Schäberle
  6. Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA

    • Slava Epstein
  7. Selcia, Ongar, Essex CM5 0GS, UK

    • Michael Jones
    • , Linos Lazarides
    •  & Victoria A. Steadman

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Contributions

K.L. and T.S. designed the study, analysed results, and wrote the paper. L.L.L. designed the study and analysed results. A.J.P. designed the study, performed compound isolation and structure determination and analysed data. B.P.C. designed the study, performed susceptibility experiments and wrote the paper. D.E.H. oversaw preclinical work including designing studies and analysing data. S.E. designed cultivation experiments and analysed data. M.J., L.L. and V.A.S. designed and performed experiments on structure determination and analysed data. I.E. and A.M. designed and performed experiments on mechanism of action. A.L.S., D.R.C., C.R.F., K.A.F., W.P.M., A.G.N., A.M.Z. and C.C. performed experiments on compound production, isolation, susceptibility testing and data analysis. T.F.S. identified the biosynthetic cluster.

Competing interests

The following authors, L. L. Ling, A. J. Peoples, A. L. Spoering, D. E. Hughes, D. R. Cohen, C. R. Felix, K. A. Fetterman, W. P. Millett, A. G. Nitti, A. M. Zullo, K. Lewis, and S. Epstein, declare competing financial interests as they are employees and consultants of NovoBiotic Pharmaceuticals.

Corresponding author

Correspondence to Kim Lewis.

Extended data

Supplementary information

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