Dokdothiocin, an Anti-Neuroinflammatory Thiopeptide from <i>Streptomyces</i> sp. 20A130

Dokdothiocin, a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the thiopeptide family, was isolated from <i>Streptomyces</i> sp. 20A130. Its structure was elucidated by extensive NMR analyses, high-resolution mass spectrometry, and chemical derivatization, revealing a 29-membered macrocyclic scaffold bearing oxazole, thiazole, and a central pyridine ring. Dokdothiocin differs from previously reported thiopeptides in macrocycle size, heterocycle arrangement, and residue-specific modifications, including the incorporation of a 3-hydroxyproline residue within the macrocyclic framework. Bioinformatic analysis of the corresponding biosynthetic gene cluster is consistent with a maturation pathway involving heterocycle formation and pyridine aromatization. Functionally, dokdothiocin attenuated lipopolysaccharide-induced activation of BV2 microglial cells by reducing nitric oxide production and suppressing NF-κB signaling, highlighting it as a structurally distinctive thiopeptide scaffold with antineuroinflammatory potential.