Fait, A.; Angst, D. C.; Stylianou, V.; Brülisauer, L.; Brugger, S. D.; Hall, A. R.

Staphylococcus aureus is an important human pathogen. With the growing threat of antimicrobial resistance, exemplified by methicillin-resistant S. aureus (MRSA) infections requiring last-line antibiotics, alternative strategies to combat S. aureus and MRSA colonisation are needed. One promising direction is to harness interactions between S. aureus and commensal bacteria resident in the nasal passage. However, it remains unclear which bacterial species or combinations are most effective at inhibiting S. aureus, and whether this inhibition is affected by resistance to last-line antibiotics. Here, we address this gap using systematic in vitro experiments to identify commensal species or combinations that inhibit MRSA, including strains resistant to key last-resort therapies. In a combinatorial screen, we detected widespread inhibition of MRSA by commensal species, with inhibitory strength dependent on species identity and community composition. Staphylococcal commensal species produced the strongest MRSA inhibition, but we achieved similarly strong inhibition by combining Corynebacterium species with Dolosigranulum pigrum. This was linked to positive growth interactions between commensals. Importantly, we observed similar levels of MRSA inhibition by commensal species when we tested MRSA strains resistant to key anti-MRSA antibiotics, including clinical isolates. Inhibition was sustained during serial passaging experiments, with minimal MRSA adaptation upon prolonged exposure. Our results show defined combinations of nasal commensals can robustly inhibit MRSA, including strains resistant to last-resort antibiotics. This supports the potential of microbiota-based therapies to prevent or eliminate S. aureus colonisation from the human nose, including in the context of antibiotic resistance.