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

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 and M. Reza Ghadiri ()
Additional contact information
Sara Fernandez-Lopez: The Scripps Research Institute
Hui-Sun Kim: The Scripps Research Institute
Ellen C. Choi: The Scripps Research Institute
Mercedes Delgado: The Scripps Research Institute
Juan R. Granja: The Scripps Research Institute
Alisher Khasanov: The Scripps Research Institute
Karin Kraehenbuehl: The Scripps Research Institute
Georgina Long: The Scripps Research Institute
Dana A. Weinberger: The Scripps Research Institute
Keith M. Wilcoxen: The Scripps Research Institute
M. Reza Ghadiri: The Scripps Research Institute

Nature, 2001, vol. 412, issue 6845, 452-455

Abstract: 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.

Date: 2001
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DOI: 10.1038/35086601

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