Beta-turn modified gramicidin S analogues containing arylated sugar amino acids display antimicrobial and hemolytic activity comparable to the natural product.
This paper describes the design and synthesis of gramicidin S (GS) analogues 10a-c containing arylated sugar amino acids (SAAs) as a replacement of one of the two (D)Phe-Pro beta-turn regions. The cyclic, amphiphilic peptides adopt a beta-sheet conformation featuring an unusual reverse turn induced by the SAAs. The altered turn region induces a slight distortion of the antiparallel beta-sheet, as compared to GS; the overall geometry however closely resembles that of the nonarylated GS analogue 1. GS analogues 10a-c proved to be as active as the parent GS itself as antibacterial agents and are equally efficient in lysing red blood cells. These properties are in sharp contrast to the diminished biological activity displayed by 1. We conclude that the presence of aromaticity in the turn regions of GS derivatives is required for biological activity, whereas the native conformation of the beta-hairpin is not. Our findings may guide future research toward efficient and nonhemolytic GS analogues for combating bacterial infections.
Grotenbreg
Gijsbert M
GM
Leiden Institute of Chemistry, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Buizert
Annelies E M
AE
Llamas-Saiz
Antonio L
AL
Spalburg
Emile
E
van Hooft
Peter A V
PA
de Neeling
Albert J
AJ
Noort
Daan
D
van Raaij
Mark J
MJ
van der Marel
Gijsbert A
GA
Overkleeft
Herman S
HS
Overhand
Mark
M
D000179:Acrylates / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000606:Amino Sugars / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001688:Biological Products / Q000138:chemical synthesis / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects*; D006096:Gramicidin / Q000138:chemical synthesis / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D017433:Protein Structure, Secondary
D000179:Acrylates; D000596:Amino Acids; D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D001688:Biological Products; D006096:Gramicidin; D010649:Phenylalanine; D011392:Proline