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Closthioamide (CTA) is a symmetric nonribosomal peptide (NRP) comprised of two diaminopropane‐linked polythioamidated monomers. CTA is biosynthesized by Ruminiclostridium cellulolyticum via an atypical NRP synthetase (NRPS)‐independent biosynthetic pathway. Although the logic for monomer assembly was recently elucidated, the strategy for the biosynthesis and incorporation of the diamine linker remained a mystery. By means of genome editing, synthesis, and in vitro biochemical assays, we demonstrate that the final steps in CTA maturation proceed through a surprising split‐merge pathway involving the dual use of a thiotemplated intermediate. This pathway includes the first examples of an aldo‐keto reductase catalyzing the reductive release of a thiotemplated product, and of a transthioamidating transglutaminase. In addition to clarifying the remaining steps in CTA assembly, our data shed light on largely unexplored pathways for NRPS‐independent peptide biosynthesis.

An Unexpected Split‐Merge Pathway in the Assembly of the Symmetric Nonribosomal Peptide Antibiotic Closthioamide