Efforts to improve the effectiveness of existing interventions for antimicrobial resistant (AMR) infections include finding new ways to overcome resistance to licenced antibiotics using adjuvants, or by using antibiotics in new combinations. While antimicrobial chemotherapy targeting the cell wall (e.g. β-lactams) remains a cornerstone of modern healthcare, resistance to these drugs presents an escalating clinical challenge. Predominantly, the safest and most effective class of antibiotics are the β-lactams, most of which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). We have discovered that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides has pleiotropic effects including significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.