Heterologous expression reveals a cryptic morphogenetic lanthipeptide durhapeptin from Streptomyces durhamensis

Morphological differentiation in Streptomyces is regulated by extracellular peptide signals, including class III lanthipeptides such as SapB and AmfS. Genome mining of Streptomyces durhamensis identified a previously uncharacterized class III lanthipeptide biosynthetic gene cluster. The precursor peptide and the modifying enzyme were heterologously expressed in Escherichia coli, enabling the production of a lanthipeptide designated durhapeptin. Mass spectrometric analyses combined with partial hydrolysis supported the presence of two labionin cross-links in the mature peptide. Functional assays demonstrated that a durhapeptin variant selectively induced aerial hyphae formation in several Streptomyces species harboring related gene clusters, whereas no activity was observed in the original producer strain or in distantly related species. Substitution of hydrophobic residues abolished morphogenetic activity, indicating that hydrophobicity is critical for its biological function. These findings suggest that cryptic class III lanthipeptides contribute to species-specific regulation of morphological differentiation and highlight the importance of this group of lanthipeptides in the developmental biology of streptomycetes.