Biosynthetic Potential and Antibiotic Resistance in Environmental Streptomyces across Agricultural and Natural Ecosystems

Streptomyces species play key roles in producing natural products and are important in soil and agricultural environments. The link between their biosynthetic gene clusters (BGCs) and clinically known antibiotic resistance genes (ARGs) in the environment remains poorly understood. In this study, we compared the genomes of 90 environmental Streptomyces strains from diverse agricultural and natural sites worldwide to examine how their biosynthetic capabilities and antibiotic resistance relate to their evolutionary history and environments. Phylogenomic analyses based on average nucleotide identity (ANI) revealed substantial genetic diversity with limited clustering by geographic origin or isolation source. Genome-wide prediction of biosynthetic gene clusters using GECCO revealed extensive, highly variable biosynthetic potential across genomes, with a large proportion of BGCs remaining uncharacterized. In contrast, clinically referenced ARGs identified using AMRFinderPlus and CARD were unevenly distributed and often absent, indicating limited overlap between environmental resistance mechanisms and clinical resistance determinants. Our quantitative analysis found a significant negative correlation between the total number of BGCs and the number of clinically identified ARGs (Spearman’s ρ=−0.277, P=0.0081). This result challenges the common belief that antibiotic production and clinical resistance are closely connected. When we measured antibiotic-specific biosynthetic potential using the Antibiotic Biosynthetic Potential Index (ABPI), we also found no association with ARG content, further supporting the idea that biosynthesis and clinical resistance are separate. We also observed substantial variation in both BGC and ARG content, even among closely related genomes, indicating that Streptomyces genomes are highly flexible. Overall, our findings show that biosynthetic capacity and clinically defined antibiotic resistance are separate genomic traits in environmental Streptomyces. This highlights the need for genome-based, context-aware methods to assess environmental resistance risks. It also shows that Streptomyces are a valuable source of new biosynthetic diversity for discovering natural products, improving agricultural biotechnology, and supporting One Health research.