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Repurposing zidovudine and 5-fluoro-2'-deoxyuridine as antibiotic drugs made possible by synergy with both trimethoprim and the mitochondrial toxicity-reducing agent uridine

The increasing frequency of antibiotic-resistant bacterial infections is a major public health challenge, and new antibiotic drugs are urgently needed. A rapid solution to the problem is to repurpose clinically approved compounds with antibacterial properties, such as the nucleoside analogues zidovu...

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Bibliographic Details
Published in:Journal of antimicrobial chemotherapy 2024-12
Main Authors: Levenfors, Jolanta J, Bjerketorp, Joakim, Guss, Bengt, Nord, Christina, Cao, Sha, Hughes, Diarmaid, Broberg, Anders, Öberg, Bo
Format: Article
Language:English
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Summary:The increasing frequency of antibiotic-resistant bacterial infections is a major public health challenge, and new antibiotic drugs are urgently needed. A rapid solution to the problem is to repurpose clinically approved compounds with antibacterial properties, such as the nucleoside analogues zidovudine (azidothymidine) or 5-fluoro-2'-deoxyuridine. Here we report the in vitro and in vivo antibacterial properties of double and triple combinations of azidothymidine or 5-fluoro-2'-deoxyuridine with uridine and/or trimethoprim. We determined MICs of azidothymidine and 5-fluoro-2'-deoxyuridine, alone or combined with uridine and/or trimethoprim, against a selection of Gram-negative and Gram-positive bacteria. We also measured MICs of a selection of antibiotics of different classes as a function of uridine concentration. The efficacy of azidothymidine and 5-fluoro-2'-deoxyuridine with uridine and/or trimethoprim was measured in a murine peritonitis infection model. The addition of uridine enhanced the in vitro antibacterial activity of azidothymidine and 5-fluoro-2'-deoxyuridine, against Gram-negative and Gram-positive bacteria, respectively. Uridine also enhanced the in vitro antibacterial activity of azidothymidine/trimethoprim and 5-fluoro-2'-deoxyuridine/trimethoprim combinations. Triple combinations containing azidothymidine, trimethoprim and uridine, showed antibacterial synergy against Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) whereas the 5-fluoro-2'-deoxyuridine, trimethoprim and uridine combination showed synergy against the Gram-positive Staphylococcus aureus. The positive effect of uridine on the efficacy of azidothymidine/trimethoprim combination was also observed in vivo in a murine E. coli peritonitis model. Triple combinations of these clinically approved compounds warrant further investigations as therapies to combat antibiotic-resistant infections.
ISSN:1460-2091
1460-2091
DOI:10.1093/jac/dkae438