The effect of thiol functional group incorporation into cationic helical peptides on antimicrobial activities and spectra

Nikken Wiradharma, Majad Khan, Lin Kin Yong, Charlotte Hauser, See Voon Seow, Shuguang Zhang, Yi Yan Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Antimicrobial peptides (AMP) have been proposed as blueprints for the development of new antimicrobial agents for the treatment of drug resistant infections. A series of synthetic AMPs capable of forming α-helical structures and containing free-sulfhydryl groups are designed in this study ((LLKK) 2C, C(LLKK) 2C, (LLKK) 3C, C(LLKK) 3C). In particular, the AMP with 2 cysteine residues at the terminal ends of the peptide and 2 repeat units of LLKK, i.e., C(LLKK) 2C, has been demonstrated to have high selectivity towards a wide range of microbes from Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, Pseudomonas aerogenosa, and yeast Candida albicans over red blood cells. At the MIC levels, this peptide does not induce significant hemolysis, and its MIC values occur at the concentration of more than 10 times of their corresponding 50% hemolysis concentrations (HC 50). Microscopy studies suggest that this peptide kills microbial cells by inducing pores of ∼20-30 nm in size in microbial membrane on a short time scale, which further develops to grossly damaged membrane envelope on a longer time scale. Multiple treatments of microbes with this peptide at sub MIC concentration do not induce resistance, even up to passage 10. However, the same treatment with conventional antibiotics penicillin G or ciprofloxacin easily develop resistance in the treated microbes. In addition, the peptides are shown not to induce secretion of IFN-γ and TNF-α in human monocytes as compared to lipopolysaccharide, which implies additional safety aspects of the peptides to be used as both systemic and topical antimicrobial agents. Therefore, this study provides an excellent basis to develop promising antimicrobial agents that possess a broad range of antimicrobial activities with less susceptibility for development of drug resistance.

Original languageEnglish (US)
Pages (from-to)9100-9108
Number of pages9
JournalBiomaterials
Volume32
Issue number34
DOIs
StatePublished - Dec 1 2011

Keywords

  • Antimicrobial peptides (AMP)
  • Drug resistance
  • Hemolysis
  • Membrane lysis
  • Thiol and sulfhydryl
  • α-Helix

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

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