Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic

• DOI: 10.1016/j.isci.2021.103611
• Publication Date: 2021-12-10T17:27:37Z
• Authors: Justin R. Randall; Gillian Davidson; Renee M. Fleeman; Santos A. Acosta; Ian M. Riddington; T. Jeffrey Cole; Cory D. DuPai; Bryan W. Davies
• Keywords: Cyclic peptide

The rapid development and spread of antibiotic resistance necessitate the development of novel strategies for antibiotic discovery. Symbah-1, a synthetic peptide antibiotic, was identified in a high-throughput antibacterial screen of random peptide sequences. Symbah-1 functions through membrane disruption and contains broad spectrum bactericidal activity against several drug-resistant pathogens. Circular dichroism and high-resolution mass spectrometry indicate symbah-1 has a β-hairpin structure induced by lipopolysaccharide and is cyclized via an intramolecular disulfide bond. Together these data classify symbah-1 as an uncommon synthetic member of the β-hairpin antimicrobial peptide class. Symbah-1 displays low hemolysis but loses activity in human serum. Characterization of a symbah-1 peptide library identified two variants with increased serum activity and protease resistance. The method of discovery and subsequent characterization of symbah-1 suggests large synthetic peptide libraries bias toward macrocyclic β-hairpin structure could be designed and screened to rapidly expand and better understand this rare peptide antibiotic class.