Large-scale insights into the biosynthetic potential of the Bacillus cereus group

Bacterial secondary metabolites (SMs) are a critical source of natural product-derived drugs. However, SM discovery efforts have focused overwhelmingly on Actinomycetes, potentially overlooking other key producers. Here, we explore the biosynthetic potential of the Bacillus cereus group, an underexplored complex of SM producers. Using a combined rule- and machine learning-based approach, we mine an unprecedented number of B. cereus group genomes (n = 9,744) for SM-producing biosynthetic gene clusters (BGCs; n = 200,196). Notably, 158,678 B. cereus group BGCs (78.2%) did not cluster with previously described BGCs, suggesting new chemical scaffolds to be explored. B. pseudomycoides was particularly prolific in terms of its SM production potential (30.8 BGC families/genome, Kruskal-Wallis p < 0.0001), and we identify a previously uncharacterized, B. pseudomycoides-unique peptide. Overall, our study represents the largest survey of B. cereus group biosynthetic potential to date and posits the complex as an under-queried SM resource.