Regulatory Genesas Beacons for Discovery and Prioritizationof Biosynthetic Gene Clusters in <i>Streptomyces</i>

Actinobacteria are renowned for their ability to produce a wide range of bioactive molecules, including many anticancer compounds and antibiotics that are critical in the battle against antimicrobial resistance. Despite identification of a vast array of biosynthetic gene clusters (BGCs) through genome mining, much of this biosynthetic potential remains unexplored, partially due to the fact that many remain silent or cryptic under typical laboratory conditions. Regulatory networks can provide clues to the location of yet undiscovered gene cluster families or be leveraged to predict their expression. Here, we investigate the associations between regulatory genes and BGCs to uncover their predictive capabilities in discovering and prioritizing gene clusters for downstream wet-lab validation. By analyzing the protein domain architectures of 128,993 potential regulators derived from 440 complete <i>Streptomyces</i> genomes, we uncovered various associations between biosynthetic classes, biological activities of their products, and regulator families. Specifically, subsets of the <i>Streptomyces</i> Antibiotic Regulatory Protein (SARP) and LuxR families were strongly associated with biosynthetic pathways encoding the production of bioactive compounds. After closer genomic inspection of the small SARPs, we discovered 82 putative SARP-associated BGCs that escaped detection by state-of-the-art software. This shows that continued exploration of regulatory systems will not only deepen our understanding of Actinobacteria’s biosynthetic capabilities but also facilitates discovery and prioritization of high-potential BGCs in future genome-mining applications.