Unlocking the biosynthetic potential of Paenibacilli through a genus-wide exploration of gene clusters for secondary metabolite production

The genus Paenibacillus is a prolific producer of secondary metabolites with diverse ecological and industrial applications. However, a comprehensive overview of the biosynthetic gene cluster (BGC) diversity and distribution throughout the genus has been limited. Here, we performed large-scale genome mining on 284 high-quality genomes and generated a non-redundant dataset of 126 representative genomes to explore the biosynthetic potential of this genus. A total of 3,273 BGCs were identified from the 284 genomes that clustered into 1,013 gene cluster families (GCFs), with 98.7% classified as unknown, indicating vast potential for novel secondary metabolite discovery in the Paenibacillus genus. Comparative analysis revealed significant phylogenetic and clade-specific distribution patterns of GCFs, with certain clades enriched in unique biosynthetic pathways while others exhibited low similarity to known BGCs, suggesting evolutionary adaptation to diverse ecological niches. This study uncovers the rich and largely untapped biosynthetic potential of the genus Paenibacillus, providing a foundation for future exploration of its natural products and their applications in biotechnology and medicine. IMPORTANCEBacterial secondary metabolites have been instrumental in the development of antibiotics, antifungals, and other bioactive compounds. The genus Paenibacillus is an underexplored source of such metabolites, with significant potential for novel discoveries. By integrating genome mining and phylogenetic analysis, this study systematically characterizes the diversity, distribution, and novelty of biosynthetic gene cluster across the genus. The identification of clade-specific biosynthetic patterns and numerous unknown gene cluster families highlights Paenibacillus as a promising target for uncovering novel compounds with ecological and therapeutic relevance. These findings not only expand our understanding of bacterial secondary metabolite biosynthesis but also offer new opportunities for the development of sustainable biotechnological applications.