title: 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.
authors: Department of Chemistry, Toho University, Funabashi, Chiba 274–8510, Japan.
authors: Makoto
authors: M
authors: Tamaki
authors: Kazumasa
authors: K
authors: Takanashi
authors: Takuji
authors: T
authors: Harada
authors: Kenta
authors: K
authors: Fujinuma
authors: Mitsuno
authors: M
authors: Shindo
authors: Masahiro
authors: M
authors: Kimura
authors: Yoshiki
authors: Y
authors: Uchida
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy; D002942:Circular Dichroism; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D012756:Sheep
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin