Abstract
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 Staphylococcus aureus are well characterized, the diversity across the Staphylococcus 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. Staphylococcus lugdunensis 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 Staphylococcus genus. This work provides a foundation for future experimental studies to identify the role of metallophores in microbial community interactions.