Expanding the Chemical Diversity of Grisechelins via Heterologous Expression

Thiazole
scaffold-based small molecules exhibit a range of biological
activities and play important roles in drug discovery. Based on bioinformatics
analysis, a putative biosynthetic gene cluster (BGC) for thiazole-containing
compounds was identified from Streptomyces sp. SCSIO
40020. Heterologous expression of this BGC led to the production of
eight new thiazole-containing compounds, grisechelins E, F, and I–N
(1, 2, 5–10), and two quinoline derivatives, grisechelins G and H (3 and 4). The structures of 1–10, including their absolute configurations, were elucidated
by HRESIMS, NMR spectroscopic data, ECD calculations, and single-crystal
X-ray diffraction analysis. Grisechelin F (2) is a unique
derivative, distinguished by the presence of a salicylic acid moiety.
The biosynthetic pathway for 2 was proposed based on
bioinformatics analysis and in vivo gene knockout
experiments. Grisechelin E (1) displayed moderate antimycobacterial
activity against Mycobacterium tuberculosis H37Ra
(MIC of 8 μg mL–1).