NosP-Regulated Nosiheptide Production Responds to Both Peptidyl and Small-Molecule Ligands Derived from the Precursor Peptide.

Nosiheptide, an archetypal member of thiopeptide antibiotics, arises from post-translational modifications of a ribosomally synthesized precursor peptide that contains an N-terminal leader peptide (LP) sequence and a C-terminal core peptide (CP) sequence. Despite extensive efforts concerning the biosynthesis of thiopeptide antibiotics, the regulatory mechanisms in this process remain poorly understood. Using the nosiheptide-producing Streptomyces actuosus strain as a model system, we report here that NosP, a Streptomyces antibiotic regulatory protein, serves as the only cluster-situated regulator and activates the transcription of all structural genes, which are organized into two divergently transcribed operons in the nos cluster, by binding to their intergenic region. NocP, the counterpart of NosP in Nocardia sp., regulates the production of structurally related nocathiacin I in a similar manner. NosP activity senses the nosiheptide biosynthetic process by interactions with both peptidyl and small-molecule ligands that result from the LP and CP parts of the precursor peptide, respectively.