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Glycine Substitution Reduces Antimicrobial Activity and Helical Stretch of diPGLa-H in Lipid Micelles

M-A Sani1, C Saenger1, D Juretic2

  • 1School of Chemistry, Bio21 Institute, University of Melbourne , Victoria 3010, Australia.

The Journal of Physical Chemistry. B
|April 21, 2017
PubMed

Insights

Antimicrobial peptides (AMPs) offer therapeutic potential against antibiotic resistance. Modified peptides like DiPGLa-H and Kiadin show enhanced antibacterial activity with low human cell toxicity, paving the way for selective drug design.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • The increasing threat of antibiotic resistance necessitates novel therapeutic strategies.
  • Antimicrobial peptides (AMPs) are a promising class of therapeutics, but their clinical application is limited by the need for improved specificity and reduced toxicity.
  • PGLa-H, a decapeptide, exhibits moderate antibacterial and low hemolytic activity, sharing sequence identity with the selective AMP PGLa.

Purpose of the Study:

  • To investigate the potential of modified antimicrobial peptides (AMPs) for enhanced therapeutic applications.
  • To evaluate the antibacterial efficacy and human cell toxicity of DiPGLa-H and Kiadin, analogues of PGLa-H.
  • To elucidate the structural basis for the improved activity and selectivity of these modified AMPs.

Main Methods:

  • Synthesis and in vitro testing of DiPGLa-H and Kiadin against Gram-negative and Gram-positive bacteria.
  • Assessment of hemolytic activity and general toxicity towards human cells.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to study peptide structure and dynamics in the presence of sodium dodecyl sulfate (SDS) micelles.

Main Results:

  • DiPGLa-H and Kiadin demonstrated significantly improved in vitro bactericidal activity compared to PGLa-H against a range of pathogens.
  • Both modified peptides exhibited generally low toxicity towards human cells, indicating improved selectivity.
  • NMR studies revealed minimal structural differences in the N-terminal regions but greater C-terminal flexibility in Kiadin, leading to a tighter structure in micellar environments.

Conclusions:

  • Sequential tandem repeats and specific amino acid substitutions (e.g., Val to Gly) can enhance the antibacterial potency and selectivity of AMPs.
  • Subtle conformational changes, influenced by amino acid modifications and environmental conditions, are crucial for optimizing AMP function.
  • These findings highlight the potential of rational design, based on understanding structure-activity relationships, to develop next-generation antimicrobial peptide therapeutics.

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