Design of an α-helical antimicrobial peptide with improved cell-selective and potent anti-biofilm activity

Abstract

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.

Antimicrobial and anti-inflammatory activities of three chensinin-1 peptides containing mutation of glycine and histidine residues

“…Compared with the parent peptide chensinin-1, the mutated peptides MC1-1, MC1-2, and MC1-3 demonstrated potent antimicrobial activities against all tested Gram-positive bacteria, with different activities against specific Gram-negative bacteria. To evaluate the overall antimicrobial activity, the geometric mean of the MIC values was calculated28. MC1-2 displayed much higher antimicrobial activity against the selected bacteria than MC1-1 and MC1-3.…”

Design of pH‐sensitive peptides from natural antimicrobial peptides for enhancing polyethylenimine‐mediated gene transfection

“…Mel possesses notoriously high lytic activity at both pH 7.4 and 5.0, whereas RV exhibits lower cytotoxic activity at pH 7.4 than Mel . The impact of Glu replacement on the ability of Mel and RV to disrupt the cell membrane was investigated by hemolytic assays.…”

“…Mel is an AMP with high lytic activity at neutral pH . The hemolysis assay demonstrated that 1.25 μM Mel induced 73% hRBC lysis at pH 7.4; however, 10 μM Mel induced lysis of only 50% hRBCs at pH 5.0.…”

“…Mel possesses notoriously high lytic activity at both pH 7.4 and 5.0, 31 whereas RV exhibits lower cytotoxic activity at pH 7.4 than Mel. 32 The…”

“…Mel is an AMP with high lytic activity at neutral pH. 32 The The physicochemical characteristics of the polyplexes, such as the size and the zeta potential of the polyplexes, play pivotal roles in determining the gene delivery efficiency both in vitro and in vivo. 46 In the present study, DNA gel retardation assays indicated that negatively-charged aMel or aRV would not affect the binding ability of PEI to plasmid DNA ( Figure 6).…”