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Antibacterial agents based on the cyclic d,l-α-peptide architecture

Nature volume 412, pages 452–455 (2001)Cite this article

A Corrigendum to this article was published on 15 November 2001

Abstract

The rapid emergence of bacterial infections that are resistant to many drugs underscores the need for new therapeutic agents1,2,3. Here we report that six- and eight-residue cyclic d,l-α-peptides act preferentially on Gram-positive and/or Gram-negative bacterial membranes compared to mammalian cells, increase membrane permeability, collapse transmembrane ion potentials, and cause rapid cell death. The effectiveness of this class of materials as selective antibacterial agents is highlighted by the high efficacy observed against lethal methicillin-resistant Staphylococcus aureus infections in mice. Cyclic d,l-α-peptides are proteolytically stable, easy to synthesize, and can be derived from a potentially vast membrane-active sequence space. The unique abiotic structure of the cyclic peptides and their quick bactericidal action may also contribute to limit temporal acquirement of drug resistant bacteria. The low molecular weight d,l-α-peptides offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging infectious diseases.

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Figure 1: The β-sheet-like, hydrogen-bonded tubular architecture of the self-assembled, eight-residue cyclic d,l-α-peptide, and modes of membrane permeation accessible to peptide nanotubes.
Figure 2: Rates of membrane depolarization of intact S. aureus (ATCC 25923) on exposure to self-assembling peptides.
Figure 3: In vivo antibacterial efficacy of peptide nanotubes determined by survival rates of treated versus untreated mice challenged with lethal doses of methicillin-resistant S. aureus.

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Acknowledgements

We thank M. Couto for his guidance and assistance with the in vivo studies. We are also grateful for the predoctoral fellowships from the Skaggs Research Institute and the Spanish Ministry of Education (S.F.-L.), and postdoctoral fellowships awarded by the Fulbright Program (G.V.L.), National Institutes of Health (D.A.W.), Swiss National Science Foundation (K.K.), and the Spanish Ministry of Education (M.D.). This work was supported by a grant to M.R.G. from the National Institutes of Health.

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Author notes

  1. Juan R. Granja

    Present address: Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15706, Santiago de Compostela, Spain

  2. M. Reza Ghadiri: Correspondence and requests for materials should be addressed to M.R.G.

Authors and Affiliations

  1. Departments of Chemistry and Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Sara Fernandez-Lopez, Hui-Sun Kim, Ellen C. Choi, Mercedes Delgado, Juan R. Granja, Alisher Khasanov, Karin Kraehenbuehl, Georgina Long, Dana A. Weinberger, Keith M. Wilcoxen & M. Reza Ghadiri

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Correspondence to M. Reza Ghadiri.

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Fernandez-Lopez, S., Kim, HS., Choi, E. et al. Antibacterial agents based on the cyclic d,l-α-peptide architecture. Nature 412, 452–455 (2001). https://doi.org/10.1038/35086601

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