Novel Cycloundecapeptides Related to Gramicidin S with Both High Antibiotic Activity and Low Hemolytic Activity

To find candidates with high antimicrobial and low hemolytic activities, many gramicidin S (GS) analogs of various ring sizes have been designed and synthesized. However, syntheses of antimicrobially active analogues of GS having a disordered symmetry structure from C2 have almost never been reported, because the stable, amphiphilic β-sheet structure of GS with C2 symmetry is considered essential for its strong antibacterial activity. In the present studies, novel thirteen cycloundecapeptides 1—13 related to GS were synthesized and examined. Among them, cyclo(-Va11-Orn2-Leu3-D-Phe4-X5-Pro6-Val7-Orn8-Leu9-D-Phe10-Pro11-) (X=Lys (10), Orn (11), Arg (12) and Lys(Lys) (13)) resulted in high antibiotic activity against both Gram-positive and Gram-negative microorganisms tested. In addition, 11 showed low toxicity against sheep blood cells compared with that of GS. Further, circular dichroism (CD) spectra of 10—13 had a curve similar to each other, suggesting that the conformations of these analogues in methanol are similar to each other. However, CD spectra of 10—13 were different from that of GS in the 190—210 nm region. These results suggest that the presences of one added amino acid residue at position 5 of 10—13 might be partially effective through a structural change in the biological activity of 10—13. In addition, the structural modifications at position 5 lower the undesirable hemolytic activity and enhance the desirable antibiotic activity.