Université de Lyon, 69008 Lyon, France.
Eur J Clin Microbiol Infect Dis. 2011 Oct;30(10):1249-56. doi: 10.1007/s10096-011-1220-3. Epub 2011 Apr 15.
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.
耐药菌的传播增加了对新型抗生素的需求。一些核苷类似物具有抗菌活性的观察结果促使我们进一步研究齐多夫定（AZT）的抗菌活性和耐药性。我们确定了最低抑菌浓度（MIC），研究了时间杀伤曲线，诱导了耐药菌并对胸苷激酶基因进行了测序。我们证明 AZT 对某些肠杆菌具有杀菌作用。然而，AZT 可以在大肠杆菌中诱导耐药性。这些耐药性与胸苷激酶基因的各种修饰有关。特别是，我们在两个耐药克隆中观察到该基因中存在类似于痢疾志贺菌的插入序列（IS）。在修饰胸苷激酶基因的菌株中，未观察到与经典抗生素的交叉耐药性。最后，观察到 AZT 与两种氨基糖苷类抗生素阿米卡星和庆大霉素之间存在相加或协同作用。我们证明了 AZT 的杀菌活性，并显示与庆大霉素联合具有协同作用。鉴定了耐药菌中的遗传修饰。我们的结果表明，AZT 可能有潜力添加到治疗肠杆菌感染中，或者代表开发具有更好活性和诱导更少耐药性的衍生物的基础。
