Thiazole/Oxazole‐Modified Microcins: Ribosomal Templates for Complex Natural Products

A new family of natural products has been described in which Cys, Ser/Thr from ribosomally produced peptides are converted to thiazole and oxazole heterocycles. These metabolites are now referred to as t hiazole/ o xazole‐ m odified m icrocins (TOMMs). Here, we describe a novel TOMM from Bacillus amyloliquefaciens FZB42, a gram‐positive, soil‐dwelling bacterium. Similar to microcin B17, and the virulence‐promoting toxin streptolysin S, the TOMM from FZB42 is extensively heterocyclized to become the bioactive natural product, plantazolicin (pzn). Through gene‐deletion guided isolation and mass spectrometry, our data show that a cluster of 12 genes covering 10 kb is essential for the biosynthesis of pzn. Mature pzn results from the modification of 12 out of 14 amino acid residues of a precursor peptide and represents one of the most highly posttranslationally modified peptides known. Activity profiling has demonstrated that this compounds displays ultra‐narrow spectrum antibiotic activity. Within this spectrum, we have found that Bacillus anthracis , the causative agent of anthrax, is the most susceptible. This finding not only shows that discovery opportunities within natural products research is far from over, our work sets the stage for developing highly specific countermeasures for biological warfare pathogens. Research Support: University of Illinois and NIH/NIGMS