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

Abstract

Objectives 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.Methods 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.Results 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.Conclusions Triple combinations of these clinically approved compounds warrant further investigations as therapies to combat antibiotic-resistant infections.

Published in

Journal of Antimicrobial Chemotherapy
2024
Publisher: OXFORD UNIV PRESS

SLU Authors

• Levenfors, Jolanta

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    
  • Ultupharma

• Bjerketorp, Joakim

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    
  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Ultupharma

• Guss, Bengt

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Nord, Christina

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    

• Broberg, Anders

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Cell and Molecular Biology
Pharmacology and Toxicology

Publication identifier

• DOI: https://doi.org/10.1093/jac/dkae438

Permanent link to this page (URI)

https://res.slu.se/id/publ/139903