Polycationic Gramicidin S Analogues with Both High Antibiotic Activity and Very Low Hemolytic Activity

Makoto Tamaki; Takuji Harada; Kenta Fujinuma; Kazumasa Takanashi; Mitsuno Shindo; Masahiro Kimura; Yoshiki Uchida

doi:10.1248/cpb.c12-00290

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Polycationic Gramicidin S Analogues with Both High Antibiotic Activity and Very Low Hemolytic Activity

Makoto Tamaki, Takuji Harada, Kenta Fujinuma, Kazumasa Takanashi, Mitsuno Shindo, Masahiro Kimura, Yoshiki Uchida

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Keywords: gramicidin S, polycationic analogue, high antibiotic activity, low hemolytic activity, structure–activity relationship

JOURNAL FREE ACCESS

2012 Volume 60 Issue 9 Pages 1134-1138

DOI https://doi.org/10.1248/cpb.c12-00290

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Abstract

The substitution of each constituent amino acid residue of gramicidin S (GS), cyclo(-Val^1,1′-Orn^2,2′-Leu^3,3′-D-Phe^4,4′-Pro^5,5′-)₂ with Lys residue indicated that each side chain structure of the constituent amino acid residues affect largely the antibiotic activity and hemolytic activity of GS. Further, the substitution of D-Phe^4,4′ and Pro^5,5′ residues with basic amino acid residues as a Lys residue results the high antibiotic activity and the very low hemolytic activity. Thus, we have found novel positions on the scaffold of GS at D-Phe^4,4′ and Pro^5,5′ residues whose modification will significantly increase the therapeutic index.

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