Cyclodextrin-scaffolded alamethicin with remarkably efficient membrane permeabilizing properties and membrane current conductance.
Bacterial resistance to classical antibiotics is a serious medical problem, which continues to grow. Small antimicrobial peptides represent a potential solution and are increasingly being developed as novel therapeutic agents. Many of these peptides owe their antibacterial activity to the formation of trans-membrane ion-channels resulting in cell lysis. However, to further develop the field of peptide antibiotics, a thorough understanding of their mechanism of action is needed. Alamethicin belongs to a class of peptides called peptaibols and represents one of these antimicrobial peptides. To examine the dynamics of assembly and to facilitate a thorough structural evaluation of the alamethicin ion-channels, we have applied click chemistry for the synthesis of templated alamethicin multimers covalently attached to cyclodextrin-scaffolds. Using oriented circular dichroism, calcein release assays, and single-channel current measurements, the α-helices of the templated multimers were demonstrated to insert into lipid bilayers forming highly efficient and remarkably stable ion-channels.
Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark.
Claudia U
CU
Hjørringgaard
Brian S
BS
Vad
Vladimir V
VV
Matchkov
Søren B
SB
Nielsen
Thomas
T
Vosegaard
Niels Chr
NC
Nielsen
Daniel E
DE
Otzen
Troels
T
Skrydstrup
D000408:Alamethicin / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002942:Circular Dichroism; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D007473:Ion Channels / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D018408:Patch-Clamp Techniques; D054848:Peptaibols / Q000737:chemistry; D017433:Protein Structure, Secondary
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D003505:Cyclodextrins; D007473:Ion Channels; D008051:Lipid Bilayers; D054848:Peptaibols; D000408:Alamethicin