Designing and identifying β-hairpin peptide macrocycles with antibiotic potential
Abstract
Peptide macrocycles are a rapidly emerging class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with β-hairpin structure due to weak folding properties and a propensity for aggregation. Here, we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic β-hairpin structure. Using an activity-driven high-throughput screen, we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery while also elucidating characteristics important for β-hairpin antimicrobial peptide activity.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 13, 2023
- Source ID
- 10.1126/sciadv.ade0008
Entities
People
- Bryan W Davies
- Claus O. Wilke
- Cory D DuPai
- Despoina A.I. Mavridou
- Gillian Davidson
- Justin R. Randall
- Kyra E. Groover
- Sabrina L Slater
- T. Jeffrey Cole
Organizations
- University of Texas at Austin