title: Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains.
abstract: The spread of multiresistant bacteria increases the need for new antibiotics. The observation that some nucleoside analogues have antibacterial activity led us to further investigate the antimicrobial activity and resistance of zidovudine (AZT). We determined the minimum inhibition concentration (MIC), studied time-kill curves, induced resistant bacteria and sequenced the gene for thymidine kinase. We demonstrate that AZT has a bactericidal effect on some enterobacteria. However, AZT could induce resistance in Escherichia coli. These resistances were associated with various modifications in the thymidine kinase gene. In particular, we observed the presence in this gene of an insertion sequence (IS) similar to IS911 of Shigella dysenteriae in two resistant clones. No cross-resistance with classical antibiotics in strains with modified thymidine kinase gene was observed. Finally, an additive or synergistic activity between AZT and the two aminoglycoside antibiotics amikacin and gentamicin was observed. We demonstrate the bactericidal activity of AZT and show synergy in association with gentamicin. Genetic modifications in resistant bacteria were identified. Our results indicate that AZT could potentially be added in the treatment of infections with enterobacteria or represent the basis for the development of derivatives with better activity and inducing less resistance.
authors.affiliation: Université de Lyon, 69008 Lyon, France. anne.doleans-jordheim@univ-lyon1.fr
authors.forename: A
authors.initials: A
authors.lastname: Doléans-Jordheim
authors.forename: E
authors.initials: E
authors.lastname: Bergeron
authors.forename: F
authors.initials: F
authors.lastname: Bereyziat
authors.forename: S
authors.initials: S
authors.lastname: Ben-Larbi
authors.forename: O
authors.initials: O
authors.lastname: Dumitrescu
authors.forename: M-A
authors.initials: MA
authors.lastname: Mazoyer
authors.forename: F
authors.initials: F
authors.lastname: Morfin
authors.forename: C
authors.initials: C
authors.lastname: Dumontet
authors.forename: J
authors.initials: J
authors.lastname: Freney
authors.forename: L P
authors.initials: LP
authors.lastname: Jordheim
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects*; D005839:Gentamicins / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D017422:Sequence Analysis, DNA; D012762:Shigella dysenteriae; D013211:Staphylococcus aureus / Q000187:drug effects; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005839:Gentamicins; D009153:Mutagens; D015215:Zidovudine; D000583:Amikacin; D013937:Thymidine Kinase