Lavasamycins, Glycosylated Dihydroxyanthraquinones from Streptomyces barkulensis subsp. lavasanensis Subsp. nov.

Abstract Streptomyces sp. DSM 115979T, isolated from soil collected in Lavasan (Iran), was classified as a novel subspecies of Streptomyces barkulensis, for which the name S. barkulensis subsp. lavasanensis subsp. nov. is proposed. Culture extracts yielded lavasamycin A (1) and B (2); their structures were elucidated by comprehensive HR-MS and NMR spectroscopic analyses, revealing a dihydroxyanthraquinone scaffold carrying a previously unreported N-acetyl-didesmethyl analogue of the aminodeoxysugar ossamine. Lavasamycin B (2) additionally features an unusual α,β-unsaturated γ-butenolide moiety. Lavasamycin A (1) exhibited antibacterial activity against Bacillus subtilis. Genome mining and comparative bioinformatic analyses identified the corresponding type II polyketide synthase biosynthetic gene cluster (BGC). Deletion of the ketosynthase genes lav31−lav32 abolished lavasamycin production, confirming the identity of the BGC. Inactivation of the TetR-family regulator gene lav34 resulted in substantially increased lavasamycin production, indicating pathway-specific transcriptional repression. Comparative analyses revealed similarities to angucycline and aminodeoxysugar biosynthetic pathways and enabled the proposal of a biosynthetic route to lavasamycin. In particular, the similarity of Lav15 to UrdM supports A-ring cleavage via Baeyer−Villiger oxidation. A spontaneous autoxidation likely converts 1 into 2. These findings expand the structural diversity of bacterial aromatic polyketides and highlight the biosynthetic potential of newly characterized Streptomyces taxa.