Structural characterization, derivatization, and bioactivities of secondary metabolites produced by termite-associated <i>Streptomyces lannensis</i> BYF-106

Two new C-glycoside angucycline-related analogs, urdamycin Y (<b>1</b>) and grincamycin W (<b>2</b>), as well as eight known metabolites (<b>3-10</b>), were identified from termite-associated <i>Streptomyces lannensis</i> BYF-106 based on global natural products social molecular networking (GNPS). The putative biosynthetic pathways of urdamycin Y (<b>1</b>) and grincamycin W (<b>2</b>) were proposed using bioinformatic analysis of the full genome of <i>S. lannensis</i> BYF-106. In addition, four new derivative compounds (<b>4A</b>, <b>5A</b>, <b>6A,</b> and <b>6B</b>) were synthesized via acetylation and methylation, respectively. Partial compounds were evaluated <i>in vitro</i> for antibacterial, anti-inflammatory, and cytotoxic activities. Vineomycinone B2 (<b>3</b>), fridamycin D (<b>4</b>), and 6-hydroxytetrangulol (<b>5</b>) displayed broad-spectrum antibacterial activities against <i>S. aureus</i>, methicillin-resistant <i>S. aureus,</i> and <i>P. syringae</i> pv. <i>actinidae</i>. Furthermore, urdamycin Y (<b>1</b>) exhibited potent inhibition on NO production, with an IC₅₀ value of 4.8 <i>µ</i>M, which was comparable to that of Bay11-7082 with an IC₅₀ value of 2.1 µM. Subsequently, the possible anti-inflammatory mechanism of urdamycin Y (<b>1</b>) was explored by molecular docking simulation. Finally, most of the tested metabolites showed significant cytotoxic activities against HCT-116, HT-29, and A375. Notably, 6-hydroxytetrangulol (<b>5</b>) and the acetyl derivative <b>5A</b> showed extremely strong cytotoxic activities against HCT-116, with IC₅₀ values of 9.8 and 2.2 µM, respectively. Moreover, <b>5A</b> showed extremely strong cytotoxic activity against A375 (IC₅₀ <0.2 µM), and the conceivable cytotoxic activity mechanism was also proposed by molecular docking. These findings indicated metabolites of insect-associated <i>S. lannensis</i> BYF-106 might be a potential source for developing new bioactive drugs in food, agriculture, and biomedical fields.IMPORTANCEFrequent attention to soil microorganisms has led to the rediscovery of known compounds. By contrast, insect-associated <i>Streptomyces</i> have been shown to produce a more diverse array of unique bioactive secondary metabolites compared to soil <i>Streptomyces</i>. In our ongoing effort to explore structurally diverse bioactive natural products from termite-associated <i>Streptomyces</i>, we discovered that the strain <i>S. lannensis</i> BYF-106 exhibited potent bioactivity. Chemical investigation of BYF-106 resulted in the isolation of two new C-glycoside angucycline-related analogs: urdamycin Y (<b>1</b>) and grincamycin W (<b>2</b>). In addition, four new derivative compounds (<b>4A</b>, <b>5A</b>, <b>6A</b>, and <b>6B</b>) were synthesized through acetylation and methylation, respectively. Urdamycin Y (<b>1</b>) exhibited a strong inhibitory effect on NO production, and most of the tested metabolites showed significant cytotoxic activity. These findings indicate that the metabolites of BYF-106 may offer promising avenues for the exploration and development of new bioactive drugs.