Tryptophan triggers the production of anthranilamide and quinazolinone derivatives in Streptomyces sp. PC4-3

Abstract

Streptomycetes are a valuable source of bioactive compounds, yet their biosynthetic diversity is often limited in laboratory conditions. The one strain-many compounds (OSMAC) strategy has been used to trigger the production of diverse microbial metabolites. In the present work, we observed an increased production of anthranilamide derivatives in a culture of Streptomyces sp. PC4-3 when supplemented with l-tryptophan. Three new natural products—streptotryptophin A (1), trans-streptotryptophin B (2), and cis-streptotryptophin B (3), together with three known compounds including 2,3-dihydro-2,2-dimethylquinazolin-4(1H)-one (4), nocardamine (5), and geldanamycin (6), were isolated from the tryptophan-supplemented Streptomyces culture. Structure elucidation of the isolated compounds was performed by analysis of NMR and MS data, as well as by single-crystal X-ray analysis. Compounds 2 and 3 are new natural products, and the trans and cis configurations of 2 and 3 have never been reported. We conclusively established the trans and cis configurations of 2 and 3 by single-crystal X-ray analysis, and proposed a biosynthetic pathway for compounds 1–3. A large amount (389.8 mg) of the trans isomer 2 was obtained when compared to the cis isomer 3 (15.2 mg). To our knowledge, this is the first report on the production of compounds 1–3 in nature, which is stimulated by an amino acid tryptophan. The isolated compounds did not exhibit antiviral activity against SARS-CoV-2, however, nocardamine (5) and geldanamycin (6) had antibacterial activity.