Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry

Area of Science:

• Synthetic biology
• Antimicrobial peptide design
• Tuberculosis therapeutics

Background:

• Current antimicrobials can cause collateral damage to host commensal bacteria, leading to dysbiosis.
• Precision antimicrobials are needed to target specific pathogens without disrupting the host microbiome.
• Mycobacterium tuberculosis possesses a unique, rigid outer membrane rich in mycolic acids, posing a challenge for drug penetration.

Purpose of the Study:

• To de novo design a synthetic host defense peptide with pathogen-specific targeting capabilities.
• To develop a precision antimicrobial that kills Mycobacterium tuberculosis without harming commensal bacteria or host tissues.
• To investigate the potential of this peptide to enhance antibiotic efficacy against M. tuberculosis.

Main Methods:

• Mimicked molecular features of pathogen channel-forming membrane proteins to design a synthetic peptide.
• Engineered the peptide for tryptophan-zippered assembly within the mycolic acid-rich outer membrane of M. tuberculosis.
• Assessed the peptide's specificity, mycobactericidal activity, and impact on commensal bacteria and host tissues.

Main Results:

• The designed synthetic peptide specifically targets and assembles within the M. tuberculosis outer membrane.
• The peptide demonstrated rapid mycobactericidal activity without collateral toxicity to lung commensal bacteria or host tissue.
• Mycomembrane-templated peptide assemblies enhanced the diffusion and potency of antibiotics across the M. tuberculosis envelope.

Conclusions:

• A novel biomimetic strategy successfully yielded a precision antimicrobial peptide targeting M. tuberculosis.
• This approach offers a potential solution to combat tuberculosis while preserving host microbiome integrity.
• The mycomembrane-templated assembly strategy may be applicable for designing other narrow-spectrum antimicrobial peptides.