Enzymatic Synthesis of a Polyketide/Nonribosomal Peptide Hybrid Antibiotic, Salivabactin

Salivabactin is a newly identified polyketide/nonribosomal peptide (PK/NRP) from a human oral probiotic, possessing a unique chemical structure and outstanding antibiotic activities. Although the biosynthetic gene cluster for salivabactin is known, the enzymatic logic that governs the synthesis of salivabactin has not yet been fully studied. In this work, we dissected the biosynthetic pathway for salivabactin using biochemical analysis. We successfully reconstituted the enzymatic synthesis of salivabactin in vitro, identified the minimal set of enzymes required for its biosynthesis, and revealed an unusual thioesterase domain involved in terminal olefin formation.