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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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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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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DOI: https://doi.org/10.1038/35086601
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