Using guanine to re-sensitise MRSA to methicillin: Is purine nucleotide homeostasis the Achilles' heel of MRSA antibiotic resistance?

The threat of antibiotic-resistant bacterial infections to hospital patients and the wider society continues to escalate. The discovery of antibiotics in the 1940's and 1950's represented one of the most important scientific breakthroughs in history. However since then the spread of antibiotic-resistant pathogens has gradually erooded the effectiveness of these miracle drugs. New drug development has not been able to keep pace with the emergence of so-called superbugs and a 2016 UK-government commissioned report has warned that, without intervention, infections caused by antibiotic-resistant pathogens will be responsible for more deaths than cancer in 2050.

A multipronged approach is needed to address this challenge. While new drug discovery is important, the lesson from history is that resistance always emerges to new antibiotics. Therefore, we also need to find new ways to keep our existing antibiotics working well and this is the focus of the current proposal.

Penicillin is a beta-lactam antibiotic that targets the bacterial cell wall, and can be taken orally as tablets or intravenously in hospitals. They remain among the safest and most effective antibiotics available to doctors. However resistance to beta-lactams is also widespread, which can necessitate the use of newer antibiotics like vancomycin and daptomycin that are more expensive, often less effective and have more side effects in patients. Beta-lactam antibiotics are no longer effective against the hospital superbug MRSA. However we have new evidence that exposure of MRSA to purine nucleotides (building blocks for DNA) can re-sensitise MRSA to beta-lactam antibiotics. Drugs related to purine nucelotides are already used in the treatment of cancer and viral infections. Here we will investigate how purines overcome resistance in MRSA and the potential of purine-based drugs to improve the treatment of infections caused by MRSA and other organisms on the World Health Organisation's list of priorty antibiotic-resistant pathogens.

Award Date
27 June 2019
Award Value
Principal Investigator
Professor James O'Gara
Host Institution
National University of Ireland, Galway
Investigator Led Projects