Photopharmacological Control of Cyclic Antimicrobial Peptides

• Published in: Chembiochem : a European journal of chemical biology 2018-12, Vol.19 (24), p.2591-2597
• Main Authors: Yeoh, Yuan Qi, Yu, Jingxian, Polyak, Steven W., Horsley, John R., Abell, Andrew D.
• Format: Article
• Language: English
• Subjects: amphiphilicity; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Antimicrobial peptides; Conformation; Density functional theory; Enrichment; Gramicidin; Magnetic resonance spectroscopy; NMR spectroscopy; Pathogens; Peptides; Photochemicals; photopharmacology; photoswitchable peptides; Protein structure; S. aureus; Secondary structure
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201800618

Gramicidin S is a naturally occurring antimicrobial cyclic peptide. Herein, we present a series of cyclic peptides based on gramicidin S that contain an azobenzene photoswitch to reversibly control secondary structure and, hence, antimicrobial activity. 1H NMR spectroscopy and density functional theory calculations revealed a β‐sheet/β‐turn secondary structure for the cis configuration of each peptide, and an ill‐defined conformation for all associated trans structures. The cis‐enriched and trans‐enriched photostationary states (PSSs) for peptides 1–3 were assayed against Staphylococcus aureus to reveal a clear relationship between well‐defined secondary structure, amphiphilicity and optimal antimicrobial activity. Most notably, peptides 2 a and 2 b exhibited a fourfold difference in antimicrobial activity in the cis‐enriched PSS over the trans‐enriched equivalent. This photopharmacological approach allows antimicrobial activity to be regulated through photochemical control of the azobenzene photoswitch, thereby opening new avenues in the design and synthesis of future antibiotics. A gramicidin S mimetic peptide shows a fourfold difference in the minimum inhibitory concentration against S. aureus between the cis‐enriched and trans‐enriched photostationary states. This photopharmacological approach provides an opportunity to turn antimicrobial activity “on” and “off” to allow potential future point‐of‐care applications.