Engineering Chirally Blind Protein Pseudocapsids into Antibacterial Persisters

Area of Science:

• Biotechnology
• Materials Science
• Microbiology

Background:

• Antimicrobial resistance (AMR) is a growing global health threat, necessitating novel therapeutic strategies beyond conventional antibiotics.
• Existing treatments face challenges with acquired resistance and limited efficacy against diverse bacterial phenotypes.

Purpose of the Study:

• To conceptually design and demonstrate the antimicrobial potential of protein pseudocapsids.
• To explore a novel class of antimicrobial agents effective against drug-resistant bacteria and phenotypic variants.

Main Methods:

• Utilized a combination of nanoscale and single-cell imaging techniques.
• Designed protein pseudocapsids with an icosahedral architecture, available in L and D epimeric forms.
• Investigated the mechanism of action, including membrane interaction and pore formation.

Main Results:

• Protein pseudocapsids demonstrated broad-spectrum antimicrobial activity, including against challenging bacterial strains.
• These agents were effective against phenotypic bacterial variants and cleared "superbugs" in vivo without observable toxicity.
• Mechanism involves rapid conversion into nanopores within phospholipid membranes, delivering targeted antimicrobial doses.

Conclusions:

• Protein pseudocapsids represent a promising, versatile platform for engineering novel antimicrobial agents.
• This design offers a strategy to overcome acquired resistance and address infections caused by resistant bacterial strains.
• The engineered agents exhibit structural diversity and functional persistence, paving the way for next-generation antimicrobials.