A landscape of metallophore synthesis and uptake potential of the genus <i>Staphylococcus</i>

Metallophores are secondary metabolites that enable bacterial growth in metal-limited environments such as the human nasal microbiome. While synthesis and uptake of metallophores in <i>Staphylococcus aureus</i> are well characterized, the diversity across the <i>Staphylococcus</i> genus remains unclear. We performed a comprehensive bioinformatic analysis of 77 representative species, as well as over 1800 strains, to map metallophore biosynthetic gene clusters (BGCs) and uptake systems. Staphyloferrin A (SF-A) biosynthesis was widely conserved, though disrupted loci were found in some species, with some of them appearing to have replaced SF-A with a newly discovered, still uncharacterized, BGC. In contrast, staphyloferrin B and staphylopine production were restricted to select species. Uptake systems were more broadly distributed, showing evidence of "cheating" species that lack biosynthesis, but retain the required lipoproteins for metallophore usage. <i>Staphylococcus lugdunensis</i> exemplifies this, encoding multiple uptake systems without producing known metallophores. Strain-level variation was also observed, particularly with specific cases of SF-A truncation, but also for the diversity of lipoprotein receptors. These findings highlight the diversity of metallophore systems, suggesting diverse metallophore-dependent cooperation and competition within the <i>Staphylococcus</i> genus. This work provides a foundation for future experimental studies to identify the role of metallophores in microbial community interactions.