Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA.
Sci Rep. 2020 Apr 8;10(1):6089. doi: 10.1038/s41598-020-62976-y.
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.
唑类抗真菌药是治疗侵袭性真菌病的重要治疗选择。然而，唑类耐药分离株的出现以及治疗选择的有限，给医学真菌学带来了日益严峻的挑战。为了解决这个问题，我们利用微量稀释棋盘法评估了九种二苯乙烯化合物与唑类药物协同作用的能力，特别是针对唑类耐药真菌分离株。奥昔康唑显示出最强的唑类化学增敏活性，其与伊曲康唑联合使用对白色念珠菌、耳念珠菌、新型隐球菌和烟曲霉（ΣFICI = 0.05-0.50）具有广谱协同作用。此外，在秀丽隐杆线虫感染模型中，奥昔康唑-伊曲康唑联合用药可使感染线虫中的真菌 CFU 负荷减少约 75-96%。尼罗红外排实验和 RT-qPCR 分析表明，奥昔康唑直接干扰真菌外排系统，从而使唑类药物进入真菌细胞。本研究鉴定奥昔康唑为一种新型抗真菌佐剂，可增强伊曲康唑对广泛真菌病原体的抗真菌活性。
