Resistance against frequently used antibiotics has become a major challenge in the treatment of infectious diseases. In the search for new types of antibiotics, antimicrobial peptides have attracted a lot of interest due to their activity against a broad range of Gram positive- and Gram negative bacteria, while development of resistance is minimal compared to conventional antibiotics. However, clinical application is often hampered by poor pharmacokinetics, low water solubility and poor oral bioavailability, which calls for efficient methods to modify these peptides in order to improve their pharmacological properties, as well as activity and selectivity. Herein, versatile Diels-Alder cycloadditions to naturally occurring dehydroalanines in antimicrobial peptides are described.<br/><br/>Through optimization of the Diels-Alder reaction between cyclopentadiene and a protected dehydroalanine substrate, conditions were obtained by which the thiopeptide Thiostrepton can be modified efficiently under mild and transition-metal free conditions. The reaction was performed on a preparative scale and after purification the site- and endo/exo selectivities were determined by 1D/2D 1H NMR spectroscopy techniques. Antimicrobial activity assays of the purified Diels-Alder adducts against several Thiostrepton-susceptible strains displayed MIC-values comparable to native Thiostrepton. Via efficient modification of the thiopeptide Nosiheptide and the lanthipeptide Nisin Z the generality of the method was shown. In order to demonstrate the diversity of our approach, the Diels-Alder products were also successfully subjected to Inverse-electron-demand Diels-Alder reactions with a variety of functionalized tetrazines.

Bioorthogonal modification of dehydroalanine residues in RiPPS via Diels-Alder cycloadditions

2019 Fall National Meeting

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