Discovery of New Thioviridamide-Like Compounds with Antitumor Activities

main observation and conclusion Thioviridamide is a structurally unique compound with potent antitumor activity. The biosynthesis of thioviridamide follows a typical pathway as ribosomally synthesized and post-translationally modified peptides, making the genome mining-based discovery of thioviridamide-like compounds rational. Taking advantage of the linkage between the precursor peptide and the metabolite skeleton, we identified a new biosynthetic gene cluster in Streptomyces sp. NRRL S-87 that could encode thioviridamide analogues. Overexpression of the whole gene cluster led to the isolation and structure elucidation of TVA-YJ-4 and TVA-YJ-5, two novel thioviridamide-like compounds featuring N-terminal capping groups. Chemical screening of the fermentation extracts also detected TVA-YJ-6, another new thioviridamide-like compound with representative methionine sulfoxide. Detailed analysis further revealed that these structural modifications were introduced during the compound extraction process instead of through genuine enzymatic reactions. TVA-YJ-4 and TVA-YJ-5 display slightly reduced cytotoxic activities against a panel of tumor cell lines in comparison with their parental natural product, TVA-YJ-2. Our work will expand the membership of this rare class of compounds and promote related biosynthetic studies.