Design of an α-helical antimicrobial peptide with improved cell-selective and potent anti-biofilm activity.
AR-23 is a melittin-related peptide with 23 residues. Like melittin, its high α-helical amphipathic structure results in strong bactericidal activity and cytotoxicity. In this study, a series of AR-23 analogues with low amphipathicity were designed by substitution of Ala1, Ala8 and Ile17 with positively charged residues (Arg or Lys) to study the effect of positively charged residue distribution on the biological viability of the antimicrobial peptide. Substitution of Ile17 on the nonpolar face with positively charged Lys dramatically altered the hydrophobicity, amphipathicity, helicity and the membrane-penetrating activity against human cells as well as the haemolytic activity of the peptide. However, substitution on the polar face only slightly affected the peptide biophysical properties and biological activity. The results indicate that the position rather than the number of positively charged residue affects the biophysical properties and selectivity of the peptide. Of all the analogues, A(A1R, A8R, I17K), a peptide with Ala1-Arg, Ala8-Arg and Ile17-Lys substitutions, exhibited similar bactericidal activity and anti-biofilm activity to AR-23 but had much lower haemolytic activity and cytotoxicity against mammalian cells compared with AR-23. Therefore, the findings reported here provide a rationalization for peptide design and optimization, which will be useful for the future development of antimicrobial agents.
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Shi-Kun
SK
Zhang
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Jin-Wen
JW
Song
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Feng
F
Gong
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Su-Bo
SB
Li
Department of Paediatrics, General Hospital of the PLA Rocket Force, Beijing, China.
Hong-Yu
HY
Chang
Department of Rehabilitation Center, General Hospital of the PLA, Beijing, China.
Hui-Min
HM
Xie
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Hong-Wei
HW
Gao
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Ying-Xia
YX
Tan
Department of Tissue Engineering, Beijing Institute of Transfusion Medicine, Beijing, China.
Shou-Ping
SP
Ji
D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002942:Circular Dichroism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary
D000890:Anti-Infective Agents; D010455:Peptides