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

• Published in: iScience Vol. 25; no. 1; p. 103611
• Main Authors: Randall, Justin R., Davidson, Gillian, Fleeman, Renee M., Acosta, Santos A., Riddington, Ian M., Cole, T. Jeffrey, DuPai, Cory D., Davies, Bryan W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.01.2022; Elsevier
• Subjects: Biochemistry; Microbiology; Structural biology; Microbiology; Biochemistry; Structural biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103611

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. [Display omitted] •Synthetic peptide display screen identifies a macrocyclic β-hairpin peptide antibiotic•Symbah-1 kills through disrupting bacterial membranes, yet is not very hemolytic•Symbah-1 loses activity in human serum, likely due to structural instability•Structural optimization improves its serum activity by reducing its protease lability Biochemistry; Microbiology; Structural biology