The anticancer chemotherapy drug 5-Fluorouracil has positive interaction with antibiotics and can select for antibiotic resistance in Staphylococcus aureus

Antibiotic resistance is a major global issue in healthcare and understanding the drivers of resistance is key in developing effective strategies to counter it. Many non-antibiotic drugs, such as cancer chemotherapy drugs, can have antimicrobial properties but their effects on bacteria in the context of infection and drug resistance have only recently begun to be explored. Here we investigate the antimicrobial properties of the cancer drug 5-fluorouracil (5-FU) on the common human commensal and pathogen Staphylococcus aureus. 5-FU can be metabolized by S. aureus and ultimately results in the inhibition of ThyA, involved in the folate synthesis and thymine synthesis pathways. Bacterial growth was inhibited by 5-FU, and the drug had additive or synergistic interactions with the antibiotics trimethoprim and sulfamethoxazole. The addition of thymidine overcame the inhibitory effects of 5-FU. Strains of S. aureus evolved in the presence of 5-FU developed mutations in the thymidine kinase gene tdk, likely inhibiting the thymine salvage pathway. In mixtures of clinical trimethoprim-resistant S. aureus strains and sensitive strains, the presence of 5-FU conferred a large fitness advantage to the resistant strains and selected for them over the sensitive strains. Together these data show that 5-FU has antimicrobial effects against S. aureus with these effects targeting the same pathway as existing antibiotics, and that the use of 5-FU in patients may be selecting for antibiotic-resistant bacteria.