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

Interventions

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 276 269

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 ß-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. Further, 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.

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  • James O'Gara, University of Galway, Ireland (Coordinator)
  • Barbara Kahl, University of Muenster, Germany (Partner)
  • Aras Kadioglu, University of Liverpool, United Kingdom (Partner)
  • Merve Zeden, University of Galway, Ireland (Partner)

The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health and is a growing problem. What if we could treat AMR infections with the antibiotics that we already have? Maintaining the effectiveness of existing antibiotics or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. This proposed project is focused on a novel antibiotic adjuvant. An adjuvant is a chemical or drug designed to help an antibiotic to work more effectively in the treatment of bacterial infections, including AMR infections. Our new adjuvant is a purine, one of the building blocks for DNA. Purine-based drugs are already used as anti-viral and anti-cancer agents hopefully suggesting that our novel adjuvant will be safe to use and well tolerated in patients. We will establish the therapeutic effectiveness of our purine adjuvants to restore or enhance the effectiveness of two distinct classes of antibiotics: namely penicillin-type antibiotics which target the cell wall and trimethoprim-sulfamethoxazole (TMP-SMX) which blocks folate synthesis and DNA synthesis in bacteria. Our experiments will utilise bacteria isolated from difficult-to-treat human infections including wound infections, device-related infections, osteomyelitis, endocarditis and lung infections in people with cystic fibrosis. Progress in this area has the potential to translate into short-term improvements in the treatment options for patients suffering from infections caused by AMR pathogens.

Call

2024 - Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments