Core Concepts
Heparin-binding proteins contain cryptic antimicrobial peptides that selectively target and kill gram-negative bacteria by binding to and disrupting their cell walls.
Abstract
The study investigates the hypothesis that heparin-binding proteins (HBPs) can also bind to and recognize the lipopolysaccharides (LPS) in the cell walls of gram-negative bacteria, and that these HBPs may contain cryptic antimicrobial peptide (AMP) regions that can selectively target and kill gram-negative bacteria.
The key findings are:
Using computational tools, the authors identified potential antimicrobial regions in 82% of HBPs, and found that these regions often colocalize with the heparin-binding sites containing a conserved CPC' motif.
The authors synthesized five peptides (HBP1-5) derived from these predicted antimicrobial regions and found that they exhibited strong binding affinity for both heparin and LPS, as well as potent antimicrobial activity against gram-negative bacteria like E. coli, A. baumannii, and P. aeruginosa, while being much less active against gram-positive bacteria.
Mechanistic studies showed that the HBP-derived peptides, especially HBP-4 and HBP-5, can effectively bind to and disrupt the bacterial cell wall and membrane, leading to rapid cell death.
Structural characterization revealed that binding to heparin or LPS triggers a conformational change in the peptides, promoting a more defined structure that is critical for their antimicrobial activity.
Among the peptides tested, HBP-5 emerged as the most promising candidate, exhibiting potent and selective antimicrobial activity against gram-negative bacteria, including multidrug-resistant strains, while showing low hemolytic and cytotoxic effects.
The results suggest that HBPs represent a valuable source of a new class of antimicrobial peptides that can selectively target and kill gram-negative bacteria, which are a major concern due to the rise of antibiotic resistance.
Stats
The peptides HBP-4 and HBP-5 exhibited the strongest binding affinity for both heparin and LPS.
HBP-4 and HBP-5 showed the highest antimicrobial activity against gram-negative bacteria, with MIC values in the nanomolar range.
HBP-5 displayed the highest selectivity ratio (LC50/MIC) between 50 and 800, indicating outstanding antimicrobial activity with low cytotoxicity.
Quotes
"HBPs therefore represent a source for new antimicrobials effective against antibiotic-resistant pathogens."
"HBP-5 emerges as the most attractive analog, with a selectivity ratio (LC50/MIC) between 50 and 800 (depending on bacterial strain) that must be regarded as outstanding for AMPs."