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

Abstract 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(CH 2 ) 6 CH 3 n  = 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(CH 2 ) 6 CH 3 n  = 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-NH 2 group of Pro 5 residue in GS molecule lowered the unwanted hemolytic activity and enhanced the desired antibiotic activity.