Comparative genomics of <i>Nocardia tsunamiensis</i> IFM 10818, a new source of the antibacterial macrolide nargenicin A1

Rare actinomycetes belonging to the genus <i>Nocardia</i> are opportunistic pathogens responsible for nocardiosis, especially in immunocompromised individuals. Despite their pathogenicity, they possess diverse metabolic pathways and therefore are potential sources of novel bioactive secondary metabolites, with implications for drug discovery. However, the biosynthetic potential of many <i>Nocardia</i> strains has not been determined. In this study, we evaluated the antibiotic production abilities of 119 <i>Nocardia</i> strains through co-culturing with <i>Staphylococcus aureus</i>. Among the tested strains, <i>Nocardia tsunamiensis</i> IFM 10818 exhibited strong inhibitory activity against <i>S. aureus</i>, indicating the presence of antibacterial compounds. Subsequent chemical analysis revealed that this strain produces nargenicin A1, a macrolide antibiotic previously identified in other <i>Nocardia</i> strains. To better understand the biosynthetic potential of <i>N. tsunamiensis</i> IFM 10818, we performed whole-genome sequencing. Comparative genomic analysis revealed its phylogenetic placement within the genus <i>Nocardia</i>, demonstrating its close relationship with <i>Nocardia crassostreae</i>. Importantly, we assessed the prevalence of the biosynthetic gene cluster (BGC) responsible for nargenicin A1 production within the genus. These findings confirm that <i>N. tsunamiensis</i> IFM 10818 is a previously unreported producer of nargenicin A1. This study highlights the utility of genome mining and functional screening in discovering bioactive compounds from underexplored microbial taxa. Further exploration of <i>Nocardia</i> genomes may reveal additional cryptic BGCs with pharmaceutical potential.IMPORTANCEThe macrolide nargenicin A1, produced by certain <i>Nocardia</i> strains, exhibits a range of biological activities, most notably strong antibacterial effects against methicillin-resistant <i>Staphylococcus aureus</i>. The identification of a high-yielding producer strain is essential to support future pharmaceutical development and commercial production. In this study, we identified <i>Nocardia tsunamiensis</i> IFM 10818 as a prolific producer of nargenicin A1. This strain exhibited significant inhibitory activity against <i>S. aureus</i> in co-culture assays, and a chemical analysis confirmed the production of nargenicin A1. Genome sequencing of <i>N. tsunamiensis</i> IFM 10818 allowed for the identification of the biosynthetic gene cluster responsible for nargenicin biosynthesis, reinforcing the potential for industrial applications. These findings highlight the promise of <i>Nocardia</i> species as untapped sources of valuable secondary metabolites and emphasize the importance of strain screening and genomic analyses in the discovery and development of new antibiotics.