Fatty acyl-gramicidin S derivatives with both high antibiotic activity and low hemolytic activity

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.106-109
• Main Authors: Tamaki, Makoto, Fujinuma, Kenta, Harada, Takuji, Takanashi, Kazumasa, Shindo, Mitsuno, Kimura, Masahiro, Uchida, Yoshiki
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antibacterial agents; antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Blood Cells - drug effects; chemistry; Chemistry, Pharmaceutical - methods; Dose-Response Relationship, Drug; Drug Design; Fatty acyl-gramicidin S analogue; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Gramicidin - analogs & derivatives; hemolysis; Hemolysis - drug effects; High antibiotic activity; Low hemolytic activity; Lysine - chemistry; Medical sciences; Microbial Sensitivity Tests; microorganisms; Models, Chemical; Pharmacology. Drug treatments; Sheep; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.11.062

Novel fatty acyl-gramicidin S derivatives showed the high antibiotic activity against both Gram-positive and Gram-negative microorganisms tested, and the low toxicity against sheep blood cells in comparison with that of gramicidin S. In the present study, novel eight GS derivatives having the octanoyl-(Lys)n- moieties, cyclo{-Val-Orn-Leu-d-Phe-Pro(4β-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=−H (1), and -(Lys)n-CO(CH2)6CH3n=0 (2), 1 (3), 2 (4), and 3 (5)} and cyclo{-Val-Orn-Leu-d-Phe-Pro(4α-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=−H (6), and -(Lys)n-CO(CH2)6CH3n=1 (7), and 2 (8)} were synthesized. Among them, 4, 5 and 8 result the high antibiotic activity against both Gram-positive and Gram-negative microorganisms tested. In addition, 4 and 5 showed very low hemolytic activity compared with that of GS. Thus, the introduction of the excess amino groups and the fatty acyl moiety to the γ-NH2 group of Pro5 residue in GS molecule lowered the unwanted hemolytic activity and enhanced the desired antibiotic activity.