Mining the heparinome for cryptic antimicrobial peptides that selectively kill Gram-negative bacteria

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Glycosaminoglycan (GAG)-binding proteins are crucial for cellular processes like growth and migration.
• Both GAGs and the lipid A core of Gram-negative bacteria possess negatively charged disaccharide units.
• This structural similarity suggests GAG-binding proteins might also interact with bacterial lipopolysaccharide (LPS).

Purpose of the Study:

• To investigate if GAG-binding proteins can recognize LPS and exhibit antimicrobial properties.
• To identify and characterize novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs).

Main Methods:

• Computational analysis to identify antimicrobial regions within 82% of HBPs, often co-localizing with heparin-binding sites.
• Synthesis and antimicrobial testing of five candidate peptides (HBP-1-5).
• Assessment of heparin and LPS binding affinities and structural characterization of AMPs upon binding.

Main Results:

• Novel AMPs derived from HBPs demonstrated significant activity against Gram-negative bacteria and strong LPS binding.
• A positive correlation was observed between heparin binding and LPS binding for the synthesized peptides.
• HBP-5 exhibited high affinity for both heparin and LPS, showing nanomolar antimicrobial activity against Gram-negative bacteria.

Conclusions:

• GAG-binding proteins can recognize LPS, functioning as antimicrobial proteins.
• This study introduces a new class of AMPs, particularly HBP-5, with specific efficacy against Gram-negative bacteria.
• The findings suggest a potential new therapeutic avenue for combating Gram-negative bacterial infections.