ABSTRACT
Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using ß,γ-diamino acids (ß,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects. Moreover, extensive studies revealed that CP-2 likely kills bacteria through membrane disruption. Altogether, CP-2 is a promising membrane-active antibiotic with therapeutic potential.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Gramicidin/pharmacology , Peptidomimetics/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Gramicidin/chemical synthesis , Gramicidin/chemistry , Membrane Potentials/drug effects , Microbial Sensitivity Tests , Molecular Conformation , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity RelationshipABSTRACT
We describe here the synthesis and biological activity study of a pair of diastereomeric analogues of Gramicidin S using ß,γ-diamino acids as ß-turn mimic. The synthesis of the orthogonally protected ß,γ-diamino acids was achieved in 6 steps starting from d-alanine. The analogues were then synthesized in solution phase and on solid phase. Biological activity tests showed that, compared with Gramicidin S, both analogues exerted diminished hemolytic activity while they retained interesting antibacterial activity.