Walking the fine line between intracellular and membrane activities of antibacterial peptides |
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Authors: | Molly A Bower Mare Cudic William Campbell John D Wade Laszlo Otvos |
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Institution: | (1) The Wistar Institute, Philadelphia, PA, USA;(2) Chaperone Technologies, Philadelphia, PA, USA;(3) The University of British Columbia, Vancouver, B.C, Canada;(4) Howard Florey Institute, Melbourne, Victoria, Australia |
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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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Keywords: | bacterial viability cell penetration DnaK growth inhibition protein folding |
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