Summary

Leveraging over 9,000 genomic datasets from more than 200 non-tuberculous mycobacterial (NTM) species, this study delivers unprecedented insights into NTM plasmid diversity and distribution. NTM are increasingly recognized as major opportunistic pathogens, especially in immunocompromised individuals and those with chronic lung diseases, and are difficult to treat due to intrinsic and acquired antibiotic resistance. Yet, plasmids as potential vectors of resistance and virulence genes remain poorly studied. The findings show that plasmids are common in NTM, genetically diverse, and can spread across species, indicating horizontal gene transfer—a possible driver of NTM evolution and adaptation. Although genes known to confer resistance to commonly used antimycobacterial drugs were rarely found on these elements, the study also highlights that the function of most NTM plasmid genes remains unknown. Given the clinical relevance of NTM, this study emphasizes the need for further functional studies and expanded complete genome datasets to improve our understanding and management of this emerging threat.