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

The antimicrobial resistance crisis is one of the greatest threats to human health and is threatening the slide of society into a ‘post-antibiotic’ era. Beta-lactam antibiotics remain a cornerstone of antimicrobial chemotherapy in hospitals and the wider community but are not effective against methicillin-resistant Staphylococcus aureus (MRSA). Here we propose to evaluate the potential of guanine to re-sensitise MRSA to beta-lactam antibiotics and to investigate the mechanistic basis for this new therapeutic approach. We recently identified three MRSA mutants with increased resistance to beta-lactam antibiotics: one in the pgl gene from the pentose phosphate pathway, which generates ribulose-5-phosphate for de novo nucleotide biosynthesis and two nucleotide salvage pathway mutations (in the guanosine/guanine permease gene, nupG, and the guanosine phosphorylase gene, deoD). Metabolite analysis revealed significant reductions in the intracellular pools of purines, including GTP, in the pgl, nupG and deoD mutants, which correlates with increased beta-lactam resistance. Conversely exposure to exogenous guanine completely re-sensitised MRSA to oxacillin revealing a new therapeutic possibility. This project will i. elucidate the mechanism(s) through which mutations in the pgl, nupG and deoD genes alter the structure of the peptidoglycan cell wall to increase beta-lactam resistance in MRSA, ii. Investigate the role of the GTP-controlled global regulator CodY in beta-lactam resistance, iii. determine the capacity of purine nucleotides and analogues to re-sensitise MRSA to beta-lactams targeting different penicillin-binding proteins, iv. determine the effectiveness of purines to enhance the eradication of MRSA in a mouse model of device-related infection and v. extend these experiments to clinical isolates of S. aureus and other organisms on the World Health Organisation list of priority antibiotic resistant pathogens. Using guanine to render MRSA and other priority pathogens more susceptible to beta-lactams will facilitate new treatments with lower antibiotic doses and with drug combinations that are toxic at higher concentrations.