Gramicidin S analogs having six basic amino acid residues

Gramicidin S (GS), cyclo(-Val^1,1′-Orn^2,2′-Leu^3,3′-D-Phe^4,4′-Pro^5,5′-)₂,^{1, 2, 3} is a potent cyclopeptide antibiotic isolated from Bacillus brevis. Its secondary structure has been established as an antiparallel β-sheet conformation with amphiphilicity.^{4, 5} The conformation is characteristically featured with the orientation of side chains in such a way that the charged Orn side chains are situated on one side of the molecule and the hydrophobic Val and Leu side chains are situated on the other side. The side-chain arrangement is apparently held together by a rigid conformation containing two D-Phe-Pro type II′ β-turns. It has been proposed that the principal modes of antibiotic actions result from an interaction of GS with the cell membrane of the target microorganisms. GS then adopts an antiparallel β-sheet conformation with amphiphilicity, which disrupts cell membrane.⁶ Thus, the hydrophobic Val and Leu residues have been considered to be essential for exhibiting the strong activity of GS. Therefore, syntheses of antimicrobially active analogs of GS containing amino acid residues with hydrophilic side chain in place of Val and Leu residues have not been reported yet.^{2, 3, 7, 8, 9}

In this account, we designed and synthesized novel GS analogs, cyclo(-Orn^1,1′-Orn^2,2′-Orn^3,3′-D-Phe^4,4′-Pro^5,5′-)₂ (1) and cyclo(-Lys^1,1′-Orn^2,2′-Lys^3,3′-D-Phe^4,4′-Pro^5,5′-)₂ (2), which have four basic amino acid residues (Orn and Lys residues) in place of four hydrophobic amino acid residues (Val and Leu residues), to investigate the role of amphiphilic β-sheet structure of GS for the antibiotic activity.

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