Gonzales-Perdomo M, de Castro S L, Meirelles M N, Goldenberg S
Departamento de Bioquimica e Biologia Molecular, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Antimicrob Agents Chemother. 1990 Sep;34(9):1707-14. doi: 10.1128/AAC.34.9.1707.
Bacterial topoisomerase II inhibitors (ofloxacin and its commercial derivative Tarivid, nalidixic acid, and novobiocin) were tested as blockers of Trypanosoma cruzi differentiation and proliferation. The transformation of either epimastigotes into metacyclic trypomastigotes or amastigotes into trypomastigotes was inhibited by the drugs in a dose-dependent manner. The inhibition of epimastigote differentiation was also dependent on the time of drug addition to the medium. Proliferation of T. cruzi was also blocked in a dose-dependent manner by the drugs, with the exception of novobiocin, which did not inhibit epimastigote replication and resulted in cell lysis when it was used at high concentrations. On the other hand, the transformation of amastigotes into epimastigotes in axenic culture was not inhibited; this process did not require either kinetoplast (mitochondrial) DNA replication or changes in the DNA network organization. Electron microscopy of cells treated with Tarivid (ofloxacin) showed damage to the kinetoplast, suggesting that this organelle might be the target of the drug. These results indicate that a bacterial-like topoisomerase II plays an important role in T. cruzi proliferation and differentiation.
对细菌拓扑异构酶II抑制剂（氧氟沙星及其商业衍生物泰利必妥、萘啶酸和新生霉素）进行了测试，以确定其作为克氏锥虫分化和增殖阻滞剂的效果。药物以剂量依赖性方式抑制了无鞭毛体向循环后鞭毛体的转化或无鞭毛体向锥鞭毛体的转化。无鞭毛体分化的抑制也取决于向培养基中添加药物的时间。药物还以剂量依赖性方式阻断了克氏锥虫的增殖，但新生霉素除外，它不抑制无鞭毛体的复制，且在高浓度使用时会导致细胞裂解。另一方面，在无菌培养中，无鞭毛体向无鞭毛体的转化未受抑制；这一过程既不需要动质体（线粒体）DNA复制，也不需要DNA网络组织的变化。用泰利必妥（氧氟沙星）处理的细胞的电子显微镜检查显示动质体受损，表明该细胞器可能是药物的靶点。这些结果表明，一种类似细菌的拓扑异构酶II在克氏锥虫的增殖和分化中起重要作用。
