Harnessing the Biosynthetic Diversity of Actinomycetes: Discovery of Unique Natural Products Through Comparative Genomic and Metabolic Analysis

Actinomycetes, rich in biosynthetic gene clusters (BGCs), are important sources of natural products (NPs). However, the rate of discovering novel NPs from actinomycetes has declined, indicating the need for a new strategy to obtain NPs. Herein, we present a strategy for the efficient discovery of novel NPs. First, we performed a comprehensive analysis of BGCs in actinomycetes, evaluating the average number and types of BGCs per genus to identify prolific NP producers. Our analysis revealed that certain actinomycete strains, such as those in the family Pseudonocardiaceae, possess a greater number of BGCs than Streptomyces. In addition, these strains tend to possess strain-specific BGCs compared with others. To facilitate the identification of strain-specific compounds, we developed a comparative metabolic analysis method using molecular networking. Applying this method to eight Pseudonocardiaceae strains, we successfully discovered two novel peptides, lentindoles A (1) and B (2), featuring a 6/5/6 and 6/5/5 tricyclic ring system, respectively, along with their possible biosynthetic precursor, lentindole C (3). Our result demonstrates the effectiveness of our developed strategy, which is expected to accelerate the discovery of novel NPs.