Self-Assembly of Antimicrobial Peptoids Impacts Their Biological Effects on ESKAPE Bacterial Pathogens

Area of Science:

• Biochemistry
• Materials Science
• Infectious Diseases

Background:

• Antimicrobial peptides (AMPs) are vital for combating multidrug-resistant pathogens but face challenges like toxicity and proteolysis.
• Peptoids, resistant to proteolysis, are explored as AMP mimics, with their self-assembly properties and efficacy against ESKAPE pathogens being largely unknown.

Purpose of the Study:

• To investigate the antibacterial efficacy and self-assembly characteristics of peptoid mimics of cationic antimicrobial peptides.
• To determine if self-assembly influences the antimicrobial activity of peptoids against ESKAPE pathogens.

Main Methods:

• Designed and synthesized eight self-assembling peptoid mimics and two non-assembling controls.
• Utilized small-angle X-ray scattering to characterize the self-assembled morphologies (helical bundles, ellipsoidal micelles, worm-like micelles).
• Assessed in vitro antibacterial and antibiofilm activity, and in vivo anti-abscess activity against ESKAPE pathogens.

Main Results:

• Amphipathic peptoids demonstrated diverse self-assembly in aqueous media, forming various structures.
• Many self-assembled peptoid structures exhibited significant antibacterial, antibiofilm, and anti-abscess activity.
• A correlation between self-assembly and antibacterial efficacy was observed, though not perfect; worm-like micelle structures showed reduced activity compared to others.

Conclusions:

• Self-assembling peptoids represent a promising class of antimicrobials effective against multidrug-resistant pathogens.
• Specific self-assembled morphologies, such as ellipsoidal or bundled structures, are more effective than worm-like micelles against ESKAPE pathogens.
• This study pioneers self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections, relevant for clinical applications.