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.
Natural Product