Azole antifungals are vital therapeutic options for treating invasive mycotic infections. However, the emergence of azole-resistant isolates combined with limited therapeutic options presents a growing challenge in medical mycology. To address this issue, we utilized microdilution checkerboard assays to evaluate nine stilbene compounds for their ability to interact synergistically with azole drugs, particularly against azole-resistant fungal isolates. Ospemifene displayed the most potent azole chemosensitizing activity, and its combination with itraconazole displayed broad-spectrum synergistic interactions against Candida albicans, Candida auris, Cryptococcus neoformans, and Aspergillus fumigatus (ΣFICI = 0.05-0.50). Additionally, in a Caenorhabditis elegans infection model, the ospemifene-itraconazole combination significantly reduced fungal CFU burdens in infected nematodes by ~75-96%. Nile Red efflux assays and RT-qPCR analysis suggest ospemifene interferes directly with fungal efflux systems, thus permitting entry of azole drugs into fungal cells. This study identifies ospemifene as a novel antifungal adjuvant that augments the antifungal activity of itraconazole against a broad range of fungal pathogens.

中文翻译：

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欧司米芬通过强烈干扰真菌外排活性而显示出与伊曲康唑的广谱协同相互作用。

唑类抗真菌药是治疗侵入性真菌感染的重要治疗选择。然而，结合吡咯抗性分离株的出现和有限的治疗选择对医学真菌学提出了越来越大的挑战。为了解决这个问题，我们利用微量稀释棋盘检测法评估了九种二苯乙烯化合物与唑类药物，特别是针对耐唑类真菌分离物的协同相互作用能力。欧司米芬显示出最强效的唑化学增敏作用，并且其与伊曲康唑的组合显示出对白色念珠菌，白色念珠菌，新隐球菌和烟曲霉的广谱协同相互作用（ΣFICI= 0.05-0.50）。此外，在秀丽隐杆线虫感染模型中，ospemifene-itraconazole组合可将感染的线虫中的真菌CFU负担显着降低约75-96％。尼罗河红外排试验和RT-qPCR分析表明，奥司哌米芬直接干扰真菌外排系统，从而使唑类药物进入真菌细胞。这项研究确定了欧司哌米芬是一种新型的抗真菌佐剂，可增强伊曲康唑对多种真菌病原体的抗真菌活性。