Qian Weidong, Liu Na, Lu Jiaxing, Liu Qiming, Chen Si, Wang Ting
School of Biological and Pharmaceutical Sciences, Shaanxi University of Science and Technology, Xi'an, China.
Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
Virulence. 2025 Dec;16(1):2543981. doi: 10.1080/21505594.2025.2543981. Epub 2025 Aug 19.
Despite recent advancements in antifungal therapy, the antifungal armamentarium remains limited compared to antibiotics available for bacterial infections. Developing novel and effective therapeutic strategies is imperative but challenging. One promising approach involves synergizing existing antifungals with complementary agents to enhance efficacy and reduce the required dosages. This study investigates the synergistic effect of isobavachalcone (IBC) and amphotericin B (AmB) against and , focusing on ferroptosis modulation. Ferroptosis-related markers, including glutathione (GSH), malondialdehyde (MDA), ferrous ions, and reactive oxygen species (ROS), were analyzed in model infected with . IBC (4 μg/mL) significantly lowered AmB's MIC from 1 μg/mL to 0.25 μg/mL, indicating a fourfold enhancement in potency. The IBC-AmB combination caused structural damage to , compromising membrane permeability and cell wall integrity. The combination elevated host GSH levels while reducing ferrous ions, MDA, and ROS in the infected model. Mechanistically, the treatment upregulated antioxidant/stress response genes (SKN-1, GST-4, GST-5, GPX-1, DAF-16, CNC-11) and antimicrobial peptides (NLP-29). Conversely, the pro-inflammatory pathway gene PMK-1 was downregulated. The IBC-AmB combination not only reduces the MIC of AmB by fourfold but also enhances antifungal efficacy through a multifaceted mechanism that directly targets the fungal pathogen and modulates the host response. This dual action has the potential to reduce the adverse effects of AmB and improve therapeutic outcomes in the treatment of cryptococcal infections.
尽管抗真菌治疗最近取得了进展，但与用于细菌感染的抗生素相比，抗真菌药物仍然有限。开发新的有效治疗策略势在必行，但也具有挑战性。一种有前景的方法是将现有的抗真菌药物与互补剂协同使用，以提高疗效并降低所需剂量。本研究调查了异补骨脂查耳酮（IBC）和两性霉素B（AmB）对新型隐球菌和格特隐球菌的协同作用，重点是铁死亡调节。在新型隐球菌感染的秀丽隐杆线虫模型中分析了与铁死亡相关的标志物，包括谷胱甘肽（GSH）、丙二醛（MDA）、亚铁离子和活性氧（ROS）。IBC（4μg/mL）显著将AmB的最低抑菌浓度（MIC）从1μg/mL降至0.25μg/mL，表明效力提高了四倍。IBC-AmB组合对新型隐球菌造成结构损伤，损害膜通透性和细胞壁完整性。该组合提高了宿主GSH水平，同时降低了感染的秀丽隐杆线虫模型中的亚铁离子、MDA和ROS。从机制上讲，该治疗上调了抗氧化/应激反应基因（SKN-1、GST-4、GST-5、GPX-1、DAF-16、CNC-11）和抗菌肽（NLP-29）。相反，促炎途径基因PMK-1被下调。IBC-AmB组合不仅将AmB的MIC降低了四倍，还通过多方面机制增强了抗真菌效力，该机制直接靶向真菌病原体并调节宿主反应。这种双重作用有可能减少AmB的不良反应并改善隐球菌感染治疗的疗效。
