Discovery of novel glycerolated quinazolinones from Streptomyces sp. MBT27

Actinobacteria are a major source of novel bioactive natural products. A challenge in the screening of these microorganisms lies in finding the favorable growth conditions for secondary metabolite production and dereplication of known molecules. Here, we report that Streptomyces sp. MBT27 produces 4-quinazolinone alkaloids in response to elevated levels of glycerol, whereby quinazolinones A ( 1 ) and B ( 2 ) form a new sub-class of this interesting family of natural products. Global Natural Product Social molecular networking (GNPS) resulted in a quinazolinone-related network that included anthranilic acid ( 3 ), anthranilamide ( 4 ), 4(3H)-quinazolinone ( 5 ), and 2,2-dimethyl-1,2-dihydroquinazolin-4(3 H )-one ( 6 ). Actinomycins D ( 7 ) and X2 ( 8 ) were also identified in the extracts of Streptomyces sp. MBT27. The induction of quinazolinone production by glycerol combined with biosynthetic insights provide evidence that glycerol is integrated into the chemical scaffold. The unprecedented 1,4-dioxepane ring, that is spiro-fused into the quinazolinone backbone, is most likely formed by intermolecular etherification of two units of glycerol. Our work underlines the importance of varying the growth conditions for the discovery of novel natural products and for understanding their biosynthesis.