文章基本信息

标题：Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic
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作者：Justin R. Randall ; Gillian Davidson ; Renee M. Fleeman 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：1
页码：1-19
DOI：10.1016/j.isci.2021.103611
语种：English
出版社：Elsevier
摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•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 labilityBiochemistry; Microbiology; Structural biology