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) and folate pathway (e.g. trimethoprim-sulfamethoxazole, TMP-SMX) remains a cornerstone of modern healthcare, resistance to these drugs presents an escalating clinical challenge. We recently reported that purine nucleosides are powerful antibiotic adjuvants that can resensitise methicillin resistant Staphylococcus aureus (MRSA) to β-lactams. More recently we have further identified that purine nucleosides act to downregulate thymidine levels in MRSA cells. Building on this novel mechanistic insight, our data show that purines potentiate both TMP-SMX (folate is a co-factor for thymidine biosynthesis) and 5-fluorouracil (5-FU), which also disrupts pyrimidine metabolism. These discoveries reveal that therapeutic potential of TMP-SMX/purines or 5-FU/purines alone and in combination with β-lactams against MRSA and other pathogens responsible for chronic and difficult to treat infection.