title: Synergistic antimicrobial activities of folic acid antagonists and nucleoside analogs.
abstract: The antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues. Therefore, this study was aimed at screening for nucleoside analogs that impair bacterial thymidine utilization and analyzing the combined antimicrobial activities of nucleoside analogs and folic acid antagonists in the presence of thymidine. Our screening results revealed that different nucleoside analogs, in particular halogenated derivatives of 2'-deoxyuridine, substantially impaired the bacterial utilization of extracellular thymidine in Staphylococcus aureus. Time-kill methods showed that 5-iodo-2'-deoxyuridine enhanced the extent of killing of trimethoprim-sulfamethoxazole (SXT) at 24 h against S. aureus in the presence of thymidine (200 microg/liter). While SXT (40 mg/liter) alone did not kill bacteria in the presence of thymidine, its combination with the nucleoside analog at a concentration of 8 mumol/liter showed a bactericidal effect. Moreover, 5-iodo-2'-deoxyuridine combined with SXT in the presence of thymidine showed a broad spectrum of activity against several Gram-positive and Gram-negative bacteria. In conclusion, these data provide evidence that the in vitro antimicrobial activity of SXT in the presence of thymidine can be significantly improved by combination with a nucleoside analog.
authors.affiliation: Institute of Medical Microbiology and Infection Control, Hospital of Goethe University, Paul Ehrlich Str. 40, 60596 Frankfurt/Main, Germany. Johannes.Zander@kgu.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Zander
authors.forename: Silke
authors.initials: S
authors.lastname: Besier
authors.forename: Hanns
authors.initials: H
authors.lastname: Ackermann
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wichelhaus
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D007065:Idoxuridine / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D019384:Nucleic Acid Synthesis Inhibitors; D009705:Nucleosides; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D007065:Idoxuridine; D013936:Thymidine