Helix stability confers salt resistance upon helical antimicrobial peptides.
Salt sensitivity of antimicrobial peptides poses a major obstacle in their development as novel antibiotics. Here we report the use of helix-capping motifs to confer salt resistance upon helical antimicrobial peptides. The helical content of the template peptide [RLLR](5) was almost completely destroyed at salt concentrations over 200 mm NaCl, leading to a 8-32-fold decrease in antimicrobial activity. However, the introduction of helix-capping motifs at the helix termini resulted in a structurally stable peptide, which retained membrane-permeabilizing and antimicrobial activities upon exposure to salt. Furthermore, the peptide with helix-capping motifs directly inhibited the in vivo growth of Streptococcus pyogenes, which causes localized fasciitis in mice, and prevented the necrosis of the epidermis, dermis, and subcutaneous muscle layers. Results indicate that the adoption of helix-capping motifs into salt-sensitive antimicrobial peptides provides the necessary structural stability for the peptides to permeabilize cell membranes and cause cell death at physiological salt concentrations.
Park
In Yup
IY
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.
Cho
Ju Hyun
JH
Kim
Key Sun
KS
Kim
Yun-Bae
YB
Kim
Mi Sun
MS
Kim
Sun Chang
SC
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017433:Protein Structure, Secondary; D012492:Salts / Q000494:pharmacology*; D013290:Streptococcal Infections / Q000188:drug therapy*; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000254:growth & development; D014981:Xenopus
D023181:Antimicrobial Cationic Peptides; D012492:Salts