{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:53:15Z","timestamp":1791499995484,"version":"4.3.4"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Ultupharma AB"},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2021-04814"],"award-info":[{"award-number":["2021-04814"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>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\u2032-deoxyuridine. Here we report the in vitro and in vivo antibacterial properties of double and triple combinations of azidothymidine or 5-fluoro-2\u2032-deoxyuridine with uridine and\/or trimethoprim.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We determined MICs of azidothymidine and 5-fluoro-2\u2032-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\u2032-deoxyuridine with uridine and\/or trimethoprim was measured in a murine peritonitis infection model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The addition of uridine enhanced the in vitro antibacterial activity of azidothymidine and 5-fluoro-2\u2032-deoxyuridine, against Gram-negative and Gram-positive bacteria, respectively. Uridine also enhanced the in vitro antibacterial activity of azidothymidine\/trimethoprim and 5-fluoro-2\u2032-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\u2032-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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Triple combinations of these clinically approved compounds warrant further investigations as therapies to combat antibiotic-resistant infections.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkae438","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T13:53:49Z","timestamp":1734443629000},"page":"509-517","source":"Crossref","is-referenced-by-count":8,"title":["Repurposing zidovudine and 5-fluoro-2\u2032-deoxyuridine as antibiotic drugs made possible by synergy with both trimethoprim and the mitochondrial toxicity\u2013reducing agent uridine"],"prefix":"10.1093","volume":"80","author":[{"given":"Jolanta 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