The pyridine ring is a potent pharmacophore in alkaloid natural products. Nonetheless, its biosynthetic pathways are poorly understood. Rubrolones A and B are tropolone alkaloid natural products possessing a unique tetra-substituted pyridine moiety. Here, we report the gene cluster and propose a biosynthetic pathway for rubrolones, identifying a key intermediate that accumulates upon inactivation of sugar biosynthetic genes. Critically, this intermediate was converted to the aglycones of rubrolones by non-enzymatic condensation and cyclization with either ammonia or anthranilic acid to generate the respective pyridine rings. We propose that this non-enzymatic reaction occurs via hydrolysis of the key intermediate, which possesses a 1,5-dione moiety as an amine acceptor capable of cyclization. This study suggests that 1,5-dione moieties may represent a general strategy for pyridine ring biosynthesis, and more broadly highlights the utility of non-enzymatic diversification for exploring and expanding natural product chemical space.
Actinobacteria associated with insects represent one potentially rich source of novel natural products with antifungal activity. Here, we investigated the phylogenetic diversity and community composition of actinobacteria associated with ants using a combination of culture-dependent and-independent methods. Further, we assessed the antagonistic activity against phytopathogenic fungi and identified the secondary metabolites from isolates with bioactivity. A total of 416 actinobacterial isolates were obtained from three ant species (Camponotus japonicus, Lasius fuliginosus, and Lasius flavus) located in five nests. The largest amount of isolates were observed in the head samples. 16S rRNA gene sequencing showed that the isolates were diverse and belonged to ten genera within the phylum Actinobacteria, with Streptomyces and Micromonospora comprising the most abundant genera. High-throughput sequencing analyses revealed that the actinobacterial communities were more diverse and dominated by the families Nocardioidaceae, Nocardiaceae, Dermacoccaceae, Intrasporangiaceae, and Streptomycetaceae. In addition, 52.3% of the representative isolates had inhibitory properties against phytopathogenic fungi. Chemical analysis of one Streptomyces strain led to the discovery of two known compounds and one new compound. These results demonstrated that ant-derived actinobacteria represented an underexplored bioresource library of diverse and novel taxa that may be of potential interest in the discovery of new agroactive compounds.
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