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Walking the fine line between intracellular and membrane activities of antibacterial peptides

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Abstract

Analogs of pyrrhocoricin, a proline-rich antibacterial peptide with a potential therapeutic use, show multiple actions on bacterial cells. We used a dual-fluorochrome membrane viability assay to provide evidence that the lead drug candidate, Pip-pyrr-MeArg dimer derivative, kills bacteria better than the native peptide due to an improved activity on bacterial membranes. This assay was also instrumental in documenting that activity on bacterial membranes and toxicity to human cells can be correlated, and the predominant mode of action can be changed from intracellular DnaK inhibition to membrane disintegration. Similar analyses with an alanine-scan on pyrrhocoricin identified Lys3 as a crucial player to interaction with bacterial membranes, three prolines in mid-chain position as being responsible for maintaining structural integrity and Asp2, Tyr6, Leu7, and Arg9 as putative contact points to the D-E helix of the bacterial target protein DnaK.

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Author information

Authors and Affiliations

  1. The Wistar Institute, Philadelphia, PA, USA

    Molly A. Bower & Laszlo Otvos

  2. Chaperone Technologies, Philadelphia, PA, USA

    Mare Cudic

  3. The University of British Columbia, Vancouver, B.C, Canada

    William Campbell

  4. Howard Florey Institute, Melbourne, Victoria, Australia

    John D. Wade

Authors
  1. Molly A. Bower
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  2. Mare Cudic
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  3. William Campbell
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  4. John D. Wade
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  5. Laszlo Otvos
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Bower, M.A., Cudic, M., Campbell, W. et al. Walking the fine line between intracellular and membrane activities of antibacterial peptides. Int J Pept Res Ther 10, 463–473 (2003). https://doi.org/10.1007/s10989-004-2405-8

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  • DOI: https://doi.org/10.1007/s10989-004-2405-8

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