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Pneumonia and Respiratory Infections · Journal article
mBio · September 8, 2026
Encouraging direction, but not yet definitive.
This in vitro study demonstrates that pyrimidine analogs (5-FU, 5-FUrd, gemcitabine, mitomycin C) but not the purine analog 6-thioguanine synergize with β-lactams against MRSA by suppressing cell wall precursor biosynthesis pathways, notably through repression of GlmS and amino acid metabolism. The mechanism is supported by transcriptomic, microscopic, and biochemical evidence, but clinical translation and in vivo efficacy remain untested.
In vitro mechanistic study with transcriptomic and microscopy analysis. Methicillin-resistant Staphylococcus aureus; no clinical patient population. Intervention: Pyrimidine analogs (5-fluorouracil, 5-fluorouridine, gemcitabine, mitomycin C) and purine analog (6-thioguanine), alone and combined with β-lactams (oxacillin, cloxacillin), fosfomycin, daptomycin, and rifampicin. Compared with: 6-thioguanine (purine analog) as a contrasting agent; β-lactams alone as baseline.
Pyrimidine analogs (5-FU, 5-FUrd, gemcitabine, mitomycin C) exhibited intrinsic anti-MRSA activity and potentiated β-lactams, whereas purine analog 6-thioguanine showed antagonistic effects. Pyrimidine-targeting agents repressed lysine and glutamate biosynthesis and suppressed GlmS expression, limiting UDP-GlcNAc production required for cell wall synthesis. Fluorescence microscopy confirmed that pyrimidine-targeting agents, but not 6-thioguanine, impaired peptidoglycan synthesis when combined with oxacillin.
Study design does not address clinical dosing, pharmacokinetics, toxicity, or patient-level drug interactions.
These findings suggest potential to repurpose anticancer drugs targeting pyrimidine metabolism to enhance β-lactam efficacy against MRSA, but this work is preliminary and mechanistic; clinical trials would be required before any therapeutic application. The antagonistic effect of 6-thioguanine also raises a caution that certain nucleotide-targeting drugs may impair antibiotic therapy in patients undergoing concurrent cancer treatment.
In vitro mechanistic study demonstrating synergy between pyrimidine analogs and β-lactams in MRSA via cell wall precursor pathway modulation, with potential for repurposing anticancer drugs, but requiring in vivo validation before clinical application.
As stated by the source record.
These findings suggest potential to repurpose anticancer drugs targeting pyrimidine metabolism to enhance β-lactam efficacy against MRSA, but this work is preliminary and mechanistic; clinical trials would be required before any therapeutic application. The antagonistic effect of 6-thioguanine also raises a caution that certain nucleotide-targeting drugs may impair antibiotic therapy in patients undergoing concurrent cancer treatment.
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(MRSA). We previously showed that the pyrimidine analogs 5-fluorouracil (5-FU) and 5-fluorouridine (5-FUrd) synergize with β-lactams. Here, we extended this by evaluating additional nucleotide metabolism-targeting agents. Gemcitabine (Gem) and mitomycin C (Mito), such as 5-FU and 5-FUrd, exhibited intrinsic anti-MRSA activity and potentiated β-lactams, whereas the purine analog 6-thioguanine (6-TG) showed distinct, often antagonistic effects. Transcriptomic analysis revealed that pyrimidine-targeting agents repress lysine and glutamate biosynthesis, while 6-TG induced these pathways, implicating amino acid metabolism in β-lactam potentiation. Consistent with this, pyrimidine analogs also suppressed GlmS expression, potentially limiting UDP-GlcNAc production required for cell wall synthesis, and synergized with fosfomycin. Fluorescence microscopy confirmed that the potentiation of oxacillin activity by pyrimidine-targeting agents, but not 6-TG, was accompanied by impaired peptidoglycan synthesis. Additionally, glutathione-mediated attenuation of killing implicated reactive oxygen species in the bactericidal activity of cloxacillin combinations. Finally, these agents displayed strong antibiofilm activity, further enhanced in combination with daptomycin and rifampicin. Together, these findings highlight the potential of pyrimidine analogs to potentiate cell wall-targeting antibiotics and identify an important role for modulation of cell wall precursor pathways in this anti-MRSA activity. IMPORTANCE: Drug interactions can complicate the treatment of antimicrobial-resistant infections in patients undergoing treatment for cancer, highlighting the importance of understanding the effects of anticancer drugs on pathogens such as MRSA. Here, we investigated several drugs that target nucleotide metabolism and are used to treat cancer, fungal, and viral infections, both alone and in combination with commonly used penicillin-type antibiotics. We found that pyrimidine analog drugs enhanced the activity of these antibiotics against MRSA, whereas the purine analog 6-thioguanine reduced antibiotic effectiveness. These drugs altered the bacterial cell wall and other metabolic pathways linked to antibiotic susceptibility. Our findings reveal the potential to repurpose certain anticancer drugs to improve treatment of MRSA infections while also cautioning that some drug combinations may interfere with antibiotic therapy.
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