Plantazolicin (PZN) is a recently discovered, unique polyheterocyclic natural product derived from a ribosomal peptide. PZN harbors remarkable antibiotic selectivity for the causative agent of anthrax, Bacillus anthracis. In an effort to simultaneously address the structure-activity relationship of PZN and establish the tolerance of the biosynthetic pathway towards unnatural substrates, an E. coli expression strain was engineered to heterologously produce altered PZN structures. Variant precursor peptides were generated by a biased, degenerate site-directed mutagenesis approach, and mass spectrometry was employed to screen for peptides that were posttranslationally modified and exported in vivo by the E. coli reconstituted host. From this screen, 29 novel PZN analogs were identified, exhibiting a spectrum of antibacterial potency. These variants have laid the foundation for understanding what structural aspects of PZN contribute to bioactivity. Furthermore, this study has established the boundaries of the natural biosynthetic pathway for application in future engineering efforts.

Engineering unnatural variants of plantazolicin through codon reprogramming

245th National Meeting (2013)

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