Photopharmacological control of cyclic antimicrobial peptides

Abstract

Gramicidin S is a naturally occurring antimicrobial cyclic peptide. Here we present a series of cyclic peptides based on Gramicidin S each containing an azobenzene photoswitch to reversibly control secondary structure and, hence, antimicrobial activity. 1H NMR and density functional theory (DFT) 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 (PSS) for each of peptides 1-3 were assayed against Staphylococcus aureus (S. aureus) to reveal a clear relationship between well-defined secondary structure, amphiphilicity and optimal antimicrobial activity. Most notably, peptides 2a and 2b exhibited a four-fold 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, opening new avenues in the design and synthesis of future antibiotics.