Introduction: The human microbiome is critically associated with human health and disease. One aspect of this is that antibiotic-resistant pathogens such as methicillin-resistant Staphylococcus aureus can reside within the nasal microbiota which increases the risk of infections. Epidemiological studies of the nasal microbiome have revealed positive and negative correlations between non-pathogenic species and S. aureus, but the underlying molecular mechanisms remain poorly understood. The nasal cavity is iron-limited and bacteria are known to produce iron-scavenging siderophores to proliferate in such environments. Siderophores are public goods that can be consumed by all members of a bacterial community. Accordingly, siderophores are known to mediate bacterial competition and collaboration but their role in the nasal microbiome is unknown.

Goals: We sought to assess the nature und physiological relevance of siderophore-mediated interaction between S. aureus nasal commensals.

Methods: We screened 94 nasal bacterial strains from seven genera for their capacity to produce siderophores as well as to consume the siderophores produced by S. aureus. We assessed the effects of siderophore provision and piracy on the fitness of S. aureus and use cotton rat models of nasal colonization to assess the relevance of siderophores during colonization.

Results: We found that 80% of the strains engaged in siderophore-mediated interactions with S. aureus including collaborative and competitive interactions. Non-pathogenic corynebacterial species were found to be prominent consumers of S. aureus siderophores. In co-culture experiments, consumption of siderophores by competitors reduced S. aureus growth in an iron-dependent fashion. Additionally, we show that siderophore acquisition is crucial for S. aureus nasal colonization in vivo.

Summary: Our data show a wide network of siderophore mediated interactions between the species of the human nasal microbiome and provide mechanistic evidence for inter-species competition and collaboration impacting pathogen proliferation. This opens avenues for designing nasal probiotics to displace S. aureus from the nasal cavity of humans.