Adapting antibacterial display to identify serum-active macrocyclic peptide antibiotics

Area of Science:

• Microbiology
• Drug Discovery
• Biochemistry

Background:

• Antimicrobial resistance necessitates novel antibiotic scaffolds.
• Peptides face challenges like proteolytic instability and toxicity for in vivo applications.
• Screening in physiologically relevant conditions is crucial for identifying functional antimicrobial peptides.

Purpose of the Study:

• To investigate sequence factors influencing serum activity of peptide macrocycles.
• To identify novel macrocyclic peptide antibiotics with potential for treating resistant infections.
• To evaluate the in vivo efficacy and safety of lead peptide candidates.

Main Methods:

• Adaptation of antibacterial display technology for screening in human serum.
• Screening of a peptide macrocycle library for antibacterial activity.
• Characterization of an optimized lead peptide's mechanism of action and toxicity profile.

Main Results:

• Identification of numerous new macrocyclic peptide antibiotic sequences.
• Serum activity correlated with peptide length, cationic charge, and disulfide bond number.
• An optimized peptide demonstrated Gram-negative outer membrane permeation, slow bacterial killing, and no mammalian cell toxicity.

Conclusions:

• Macrocyclic peptides represent a promising scaffold for antibiotic development.
• Screening under serum conditions identifies peptides with enhanced in vivo functionality.
• The optimized peptide exhibits therapeutic potential against antimicrobial-resistant infections.