Next-Generation Tetrazine Probes for the Reactivity-Guided Isolation of Isonitrile-Containing Natural Products

Abstract

Antimicrobial resistance (AMR), the ability of pathogens to withstand treatment with currently used medicines, poses a global threat to the health and welfare of both humans and animals. Since the pipeline for novel antibiotics remains largely underpopulated, the discovery and development of novel antibiotics, ideally with novel mechanisms of action, is crucial to ensuring the treatability of microbial infections in the future. In the past, Natural Products (NPs) have often served as antibiotics or blueprints thereof. Large proportions of the bacterial potential are currently untapped, thus the discovery of novel NPs with antimicrobial activity from bacterial origin remains a promising route to antibiotic candidates. A major drawback is the high rate of re-discovery. Hence, new approaches to NP discovery need to be explored. One approach is chemical activity guided isolation of NPs from complex extracts. Rather than focusing on biological activity, this approach targets specific chemical reactivity. Isonitrile-containing natural products (ICNPs) have been known since the 1950s. Due to their unique electronic configuration, they are known as metal-binders or metallophores. Many ICNPs were shown to function in copper homeostasis (chalkophores). This metal coordinating ability is often strictly correlated to their antibacterial activity, rendering ICNPs ideal candidates as novel antibiotics. In this work, the chemoselective tetrazine-isonitrile click reaction was employed to label and isolate ICNPs from complex bacterial extracts. A series of optimized tetrazine probes for different application scenarios was developed and tested in two bacterial extracts containing ICNPs. The chemoselectivity of a newly developed tetrazine probe was compared to two literature reported isonitrile-labelling probes.

Die Dissertation ist gesperrt bis zum 10. November 2026 !