a Pediatric Research Institute , the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University , Wenzhou , PR China.
b Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine , the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University , Wenzhou , PR China.
Free Radic Res. 2019 Jun;53(6):618-628. doi: 10.1080/10715762.2019.1610563. Epub 2019 Jun 11.
With a significant increase in the incidence of system invasive fungal infections, the limited antifungal drugs and increased frequency of cross-resistance make it necessary to explore new and effective therapeutic strategies. Combination drug therapy has become one widely used choice to alleviate this problem. Geldanamycin (GdA), as an inhibitor of Hsp90, displayed broad antifungal activity when combined with fluconazole. However, due to its cytotoxicity, the dose and duration of GdA is limited. In this study, we observed the effect of fluconazole plus GdA on resistant to azoles and amphotericin B. The results showed that this synergism led to a decrease in growth and survival rate. In addition, fluconazole combined with GdA caused mitochondrial depolarisation, disruption of plasma membrane integrity and multinucleated morphology. However, the supplement of a reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), rescued the above phenotypes. This study indicated that the oxidative stress mediated by fluconazole plus GdA played an important role in the antifungal activity, and targeting oxidative stress might extend target choices to treat fungal infections.
随着系统侵袭性真菌感染发病率的显著增加，有限的抗真菌药物和交叉耐药性的增加，使得探索新的有效治疗策略变得必要。联合药物治疗已成为缓解这一问题的广泛应用选择。格尔德霉素（GdA）作为 Hsp90 的抑制剂，与氟康唑联合使用时显示出广泛的抗真菌活性。然而，由于其细胞毒性，GdA 的剂量和持续时间受到限制。在这项研究中，我们观察了氟康唑加 GdA 对唑类和两性霉素 B 耐药的影响。结果表明，这种协同作用导致生长和存活率下降。此外，氟康唑联合 GdA 导致线粒体去极化、质膜完整性破坏和多核形态。然而，添加活性氧（ROS）清除剂 N-乙酰半胱氨酸（NAC）可挽救上述表型。本研究表明，氟康唑加 GdA 介导的氧化应激在抗真菌活性中起重要作用，靶向氧化应激可能为治疗真菌感染提供更多的靶标选择。
