Active Infection & Immunity Lungs & Breathing

Deploying PURIne adjuvants to improve the Fight against StaphYlococcus aureus AMR (PURIFY AMR)

Funder MRC (part of UKRI)
Recipient organisation University of Liverpool Source-published name: University of Liverpool
Funding £368K
Period Jul 2025 — Jul 2028

In plain English

AI plain-English summary

Purine nucleosides—molecules that cells use to build DNA—can re-sensitise drug-resistant MRSA bacteria to antibiotics that no longer work against them. This matters because infections like MRSA, which cause wound infections, bone infections, heart valve infections, and lung infections in people with cystic fibrosis, are becoming harder to treat. Standard antibiotics such as beta-lactams (penicillin-type drugs) and trimethoprim-sulfamethoxazole (TMP-SMX) are losing their effectiveness. The researchers discovered that purine nucleosides work by lowering thymidine levels inside bacterial cells, which disrupts the bacteria’s ability to resist these drugs. This opens a new route to overcome antimicrobial resistance without inventing entirely new antibiotics. If this succeeds, the impact would be practical and immediate: existing, cheap, licenced antibiotics could be used again against stubborn infections. Doctors could combine TMP-SMX or 5-fluorouracil with purines, alone or alongside beta-lactams, to treat MRSA and other resistant pathogens. The project will also uncover the precise mechanisms linking purine action to antibiotic resistance, providing a blueprint for deploying these adjuvants against other drug-resistant bacteria. This is applied research with a clear clinical target.

View original technical description
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. ß-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 beta-lactams. New preliminary data have further identified that purine nucleosides act to downregulate thymidine levels in MRSA cells. Building on this novel mechanistic insight, we revealed that purines potentiate both TMP-SMX (folate is a co-factor for thymidine biosynthesis) and 5-fluorouracil (5-FU), which also disrupts pyrimidine metabolism. In this project we propose to comprehensively evaluate the therapeutic potential of TMP-SMX/purines or 5-FU/purines alone and in combination with ß-lactams against MRSA and other pathogens responsible for wound infections, device-related infections, osteomyelitis, endocarditis and lung infections in people with cystic fibrosis. Furthermore, we will uncover their underlying mechanisms of action and link these mechanisms to antibiotic resistance. This knowledge will help us to improve the effectiveness of licensed antimicrobial drugs, and overcome resistance to ß-lactam antibiotics and TMP-SMX.

View the original record at the funder ↗

Researchers

Aras Kadioglu (Principal Investigator)

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Original classification

Research Grant

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