Novel cycloundecapeptides related to gramicidin S with both high antibiotic activity and low hemolytic activity

Abstract

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 C 2 have almost never been reported, because the stable, amphiphilic β-sheet structure of GS with C 2 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(-Va1 1-Orn 2-Leu 3-D-Phe 4-X 5-Pro 6-Val 7-Orn 8-Leu 9-D-Phe 10-Pro 11-) (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. © 2011 Pharmaceutical Society of Japan.