Antimicrobial and cytolytic properties of the frog skin peptide, kassinatuerin-1 and its L- and D-lysine-substituted derivatives

J. Michael Conlon, Bency Abraham, Sehamuddin Galadari, Floyd C. Knoop, Agnes Sonnevend, Tibor Pál

Research output: Contribution to journalArticle

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Abstract

Kassinatuerin-1, a 21-amino-acid C-terminally α-amidated peptide first isolated from the skin of the African frog Kassina senegalensis, adopts an amphipathic α-helical conformation in a membrane-mimetic solvent (50% trifluoroethanol) and shows broad-spectrum antimicrobial activity. However, its therapeutic potential is limited by its relatively high cytolytic activity against mammalian cells. The antimicrobial and cytolytic properties of a peptide are determined by an interaction between cationicity, hydrophobicity, α-helicity and amphipathicity. Replacement of the C-terminal α-amide group in kassinatuerin-1 by carboxylic acid decreased both cationicity and α-helicity, resulting in an analog with decreased potency against Escherichia coli (4-fold) and Staphylococcus aureus (16-fold). Low cytolytic activities against human erythrocytes (LD50 > 400 μM) and L929 fibroblasts (LD50 = 105 μM) were also observed. Increasing cationicity, while maintaining amphipathic α-helical character, by progressively substituting Gly7, Ser18, and Asp19 on the hydrophilic face of the α-helix with L-lysine, increased antimicrobial potency against S. aureus and Candida albicans (up to 4-fold) but also increased hemolytic and cytolytic activities. In contrast, analogs with D-lysine at positions 7, 18 and 19 retained activity against Gram-negative bacteria but displayed reduced hemolytic and cytolytic activities. For example, the carboxylic acid derivative of [D-Lys7, D-Lys18, D-Lys19]kassinatuerin-1 was active (minimum inhibitory concentration (MIC) = 6-12.5 μM) against a range of strongly antibiotic-resistant strains of E. coli but showed no detectable hemolytic activity at 400 μM and was 4-fold less cytolyic than kassinatuerin-1. However, the reduction in α-helicity produced by the d-amino acid substitutions resulted in analogs with reduced potencies against Gram-positive bacteria and against C. albicans.

Original languageEnglish (US)
Pages (from-to)2104-2110
Number of pages7
JournalPeptides
Volume26
Issue number11
DOIs
StatePublished - Nov 1 2005

Fingerprint

Anura
Lysine
Skin
Derivatives
Peptides
Lethal Dose 50
Carboxylic Acids
Candida albicans
Escherichia coli
Staphylococcus aureus
Bacteria
Trifluoroethanol
Amino Acids
Candida
Gram-Positive Bacteria
Microbial Sensitivity Tests
Amino Acid Substitution
Fibroblasts
Hydrophobicity
Gram-Negative Bacteria

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

Cite this

Antimicrobial and cytolytic properties of the frog skin peptide, kassinatuerin-1 and its L- and D-lysine-substituted derivatives. / Conlon, J. Michael; Abraham, Bency; Galadari, Sehamuddin; Knoop, Floyd C.; Sonnevend, Agnes; Pál, Tibor.

In: Peptides, Vol. 26, No. 11, 01.11.2005, p. 2104-2110.

Research output: Contribution to journalArticle

Conlon, J. Michael ; Abraham, Bency ; Galadari, Sehamuddin ; Knoop, Floyd C. ; Sonnevend, Agnes ; Pál, Tibor. / Antimicrobial and cytolytic properties of the frog skin peptide, kassinatuerin-1 and its L- and D-lysine-substituted derivatives. In: Peptides. 2005 ; Vol. 26, No. 11. pp. 2104-2110.
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abstract = "Kassinatuerin-1, a 21-amino-acid C-terminally α-amidated peptide first isolated from the skin of the African frog Kassina senegalensis, adopts an amphipathic α-helical conformation in a membrane-mimetic solvent (50{\%} trifluoroethanol) and shows broad-spectrum antimicrobial activity. However, its therapeutic potential is limited by its relatively high cytolytic activity against mammalian cells. The antimicrobial and cytolytic properties of a peptide are determined by an interaction between cationicity, hydrophobicity, α-helicity and amphipathicity. Replacement of the C-terminal α-amide group in kassinatuerin-1 by carboxylic acid decreased both cationicity and α-helicity, resulting in an analog with decreased potency against Escherichia coli (4-fold) and Staphylococcus aureus (16-fold). Low cytolytic activities against human erythrocytes (LD50 > 400 μM) and L929 fibroblasts (LD50 = 105 μM) were also observed. Increasing cationicity, while maintaining amphipathic α-helical character, by progressively substituting Gly7, Ser18, and Asp19 on the hydrophilic face of the α-helix with L-lysine, increased antimicrobial potency against S. aureus and Candida albicans (up to 4-fold) but also increased hemolytic and cytolytic activities. In contrast, analogs with D-lysine at positions 7, 18 and 19 retained activity against Gram-negative bacteria but displayed reduced hemolytic and cytolytic activities. For example, the carboxylic acid derivative of [D-Lys7, D-Lys18, D-Lys19]kassinatuerin-1 was active (minimum inhibitory concentration (MIC) = 6-12.5 μM) against a range of strongly antibiotic-resistant strains of E. coli but showed no detectable hemolytic activity at 400 μM and was 4-fold less cytolyic than kassinatuerin-1. However, the reduction in α-helicity produced by the d-amino acid substitutions resulted in analogs with reduced potencies against Gram-positive bacteria and against C. albicans.",
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T1 - Antimicrobial and cytolytic properties of the frog skin peptide, kassinatuerin-1 and its L- and D-lysine-substituted derivatives

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AU - Abraham, Bency

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AU - Sonnevend, Agnes

AU - Pál, Tibor

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N2 - Kassinatuerin-1, a 21-amino-acid C-terminally α-amidated peptide first isolated from the skin of the African frog Kassina senegalensis, adopts an amphipathic α-helical conformation in a membrane-mimetic solvent (50% trifluoroethanol) and shows broad-spectrum antimicrobial activity. However, its therapeutic potential is limited by its relatively high cytolytic activity against mammalian cells. The antimicrobial and cytolytic properties of a peptide are determined by an interaction between cationicity, hydrophobicity, α-helicity and amphipathicity. Replacement of the C-terminal α-amide group in kassinatuerin-1 by carboxylic acid decreased both cationicity and α-helicity, resulting in an analog with decreased potency against Escherichia coli (4-fold) and Staphylococcus aureus (16-fold). Low cytolytic activities against human erythrocytes (LD50 > 400 μM) and L929 fibroblasts (LD50 = 105 μM) were also observed. Increasing cationicity, while maintaining amphipathic α-helical character, by progressively substituting Gly7, Ser18, and Asp19 on the hydrophilic face of the α-helix with L-lysine, increased antimicrobial potency against S. aureus and Candida albicans (up to 4-fold) but also increased hemolytic and cytolytic activities. In contrast, analogs with D-lysine at positions 7, 18 and 19 retained activity against Gram-negative bacteria but displayed reduced hemolytic and cytolytic activities. For example, the carboxylic acid derivative of [D-Lys7, D-Lys18, D-Lys19]kassinatuerin-1 was active (minimum inhibitory concentration (MIC) = 6-12.5 μM) against a range of strongly antibiotic-resistant strains of E. coli but showed no detectable hemolytic activity at 400 μM and was 4-fold less cytolyic than kassinatuerin-1. However, the reduction in α-helicity produced by the d-amino acid substitutions resulted in analogs with reduced potencies against Gram-positive bacteria and against C. albicans.

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