Chemical Modification of Peptide Antibiotics

Antibiotic resistance is becoming a major threat to our modern-day healthcare system. Over the years, it is bacteria themselves that have proven to be a rich source of natural products that exhibit antimicrobial activity. Among these, non-ribosomal peptides (NRPs) and Ribosomally synthesized and Post-translationally modified peptides (RiPPs) have become interesting targets in the search for new antibiotics because of their high activity and lower development of resistance compared to conventional antibiotics. Yet despite their promising bioactivity profile, clinical application is hampered by their poor pharmacological properties, such as low in vivo stability and aqueous solubility, and because a detailed understanding of their mechanism of action is often lacking. The chemical modification of these peptides to make semi-synthetic structural analogs with improved properties is a promising approach to overcome these obstacles.

The research described in this thesis aimed at the selective chemical modification of dehydroalanine (Dha) residues in peptide antibiotics with an emphasis on first-row transition metal catalysis. The primary focus of the research was to develop new methods for the late-stage chemical editing of RiPPs via their uniquely reactive Dha residues. The potential of these methods for improving the pharmacological properties of RiPPs and their application in the labeling and targeting of these peptides was also investigated. Another objective was to characterize newly discovered NRPs in order to aid in the development of a method for the systematic discovery and isolation of novel antimicrobial peptides from microorganisms.