The increasing resistance of Candida species to azoles emphasizes the urgent need for new antifungal agents with novel mechanisms of action. The aim of this study was to examine the effect of three DNA topoisomerase inhibitors of plant origin (camptothecin, etoposide and curcumin) on the growth of Candida dubliniensis. The phylogenetic analysis showed a close relationship between the topoisomerase enzymes of C. dubliniensis and Candida albicans. The alignment of the amino acid sequences of topoisomerase I and II of yeasts and humans evidenced conserved domains. The docking study revealed affinity of the test compounds for the active site of topoisomerase I and II in C. dubliniensis. Curcumin and camptothecin demonstrated a stronger in vitro antifungal effect than the reference drugs (fluconazole and itraconazole). Significant synergistic activity between the topoisomerase inhibitors and fluconazole at the highest concentration (750 µM) was observed. Fluconazole induced the petite phenotype to a greater degree than the topoisomerase inhibitors, indicating a tendency to generate resistance. Lower toxicity was found for such inhibitors versus reference drugs on Galleria mellonella larva. The topoisomerase inhibitors exhibited promising antifungal activity, and the DNA topoisomerase enzymes of C. dubliniensis proved to be an excellent model for evaluating new antifungal compounds.

中文翻译：

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应用于都柏林念珠菌的 DNA 拓扑异构酶 I 和 II 抑制剂可降低生长、活力、小突变体的产生和毒性，同时与氟康唑协同作用

念珠菌对唑类的耐药性不断增加，这强调了对具有新作用机制的新型抗真菌剂的迫切需求。本研究的目的是检查三种植物来源的 DNA 拓扑异构酶抑制剂（喜树碱、依托泊苷和姜黄素）对都柏林念珠菌生长的影响。系统发育分析表明，都柏林念珠菌的拓扑异构酶与白色念珠菌有密切的关系。酵母和人类拓扑异构酶 I 和 II 的氨基酸序列的比对证明了保守结构域。对接研究揭示了测试化合物对 C. dubliniensis 中拓扑异构酶 I 和 II 的活性位点的亲和力。姜黄素和喜树碱显示出比参考药物（氟康唑和伊曲康唑）更强的体外抗真菌作用。观察到拓扑异构酶抑制剂和氟康唑在最高浓度 (750 µM) 之间的显着协同活性。氟康唑比拓扑异构酶抑制剂更大程度地诱导了娇小的表型，表明有产生抗药性的趋势。与参考药物相比，此类抑制剂对大毒蛾幼虫的毒性较低。拓扑异构酶抑制剂表现出良好的抗真菌活性，而 C. dubliniensis 的 DNA 拓扑异构酶被证明是评估新抗真菌化合物的极好模型。与参考药物相比，此类抑制剂对大毒蛾幼虫的毒性较低。拓扑异构酶抑制剂表现出良好的抗真菌活性，而 C. dubliniensis 的 DNA 拓扑异构酶被证明是评估新抗真菌化合物的极好模型。与参考药物相比，此类抑制剂对大毒蛾幼虫的毒性较低。拓扑异构酶抑制剂表现出良好的抗真菌活性，而 C. dubliniensis 的 DNA 拓扑异构酶被证明是评估新抗真菌化合物的极好模型。