Helical antimicrobial polypeptides with radial amphiphilicity

Area of Science:

• Biochemistry
• Materials Science
• Microbiology

Background:

• Traditional alpha-helical antimicrobial peptides (AMPs) often exhibit facial amphiphilicity, leading to potential issues like blood protein interactions and self-aggregation due to exposed hydrophobic regions.
• These limitations hinder the therapeutic application of conventional AMPs, necessitating the development of alternative structures with improved properties.

Purpose of the Study:

• To design and characterize a new class of antimicrobial polypeptides with radial amphiphilicity.
• To evaluate their antimicrobial activity, safety profile, and potential as adjuvants for existing antibiotics.

Main Methods:

• Synthesis of cationic, helical homo-polypeptides with a distinct hydrophobic internal core and a charged exterior shell, creating radial amphiphilicity.
• Assessment of antimicrobial activity against Gram-positive and Gram-negative bacteria.
• Evaluation of hemolytic activity to determine cytotoxicity towards eukaryotic cells.
• Testing the efficacy of these polypeptides as adjuvants in combination with commercial antibiotics.

Main Results:

• The radially amphiphilic polypeptides demonstrated effective binding to negatively charged bacterial surfaces, resulting in high antimicrobial activity against a broad spectrum of bacteria.
• A significant reduction in non-specific interactions with eukaryotic cells was observed, indicated by low hemolytic activity.
• The charged exterior effectively shielded the hydrophobic core, enhancing resistance to proteolytic degradation.
• When used as adjuvants, these polypeptides improved antibiotic permeation and boosted antimicrobial efficacy by one to two orders of magnitude.

Conclusions:

• The developed radially amphiphilic polypeptides offer an innovative structural design for antimicrobial agents, overcoming limitations of traditional AMPs.
• Their unique structure provides a favorable safety profile and potent antimicrobial efficacy, suggesting their potential for treating drug-resistant bacterial infections.
• These polypeptides represent a promising platform for developing next-generation antimicrobial therapies and antibiotic adjuvants.