Oncocin (VDKPPYLPRPRPPRRIYNR-NH2): a novel antibacterial peptide optimized against gram-negative human pathogens

Area of Science:

• Microbiology
• Peptide Chemistry
• Drug Discovery

Background:

• Small proline-rich antimicrobial peptides (AMPs) are of interest due to their non-lytic mechanisms targeting intracellular bacterial components.
• Existing AMPs face challenges with stability and broad-spectrum efficacy against Gram-negative pathogens.

Purpose of the Study:

• To develop and characterize a novel antimicrobial peptide, oncocin, optimized for treating Gram-negative bacterial infections.
• To evaluate the stability, toxicity, and mechanism of action of oncocin derivatives.

Main Methods:

• Minimal inhibitory concentrations (MICs) were determined for 34 Gram-negative bacterial strains.
• Oncocin derivatives were synthesized with arginine-to-ornithine substitutions to enhance serum half-life.
• Cytotoxicity assays, hemolysis tests, quartz crystal microbalance, and fluorescence microscopy were used to assess peptide behavior and uptake.

Main Results:

• Oncocin exhibited potent activity against Enterobacteriaceae and nonfermenters (e.g., E. coli, P. aeruginosa, A. baumannii) with MICs ranging from 0.125 to 8 µg/mL.
• Arginine-to-ornithine substitutions increased serum half-life from ~20 min to >180 min and improved activity.
• Optimized oncocin derivatives showed no toxicity to human cell lines or erythrocytes, penetrated lipid membranes without lysis, and entered the bacterial periplasmic space.

Conclusions:

• Optimized oncocin derivatives are highly effective against Gram-negative pathogens with improved stability and safety profiles.
• The non-lytic, membrane-penetrating mechanism and rapid intracellular entry make oncocin a promising lead compound for novel antibacterial drug development.