The Translational Genomics Research Institute North, Flagstaff, Arizona, USA.
Beckman Research Institute of the City of Hope, Duarte, California, USA.
Microbiol Spectr. 2024 Oct 3;12(10):e0100824. doi: 10.1128/spectrum.01008-24. Epub 2024 Aug 20.
Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth and determined IC values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease.
Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.
需要找到治疗严重和难治性球孢子菌病（山谷热）的改进方法。这种地方性真菌病在北美和南美很常见，在过去 30 年中，病例数量大幅增加。目前的标准治疗方法是口服氟康唑，但这种方法常常无法完全消除感染；然而，确定治疗山谷热有效的新化合物的成本很高，这是改善治疗的一个障碍。因此，重新利用现有的药物与氟康唑治疗相结合是一个有吸引力的选择。我们筛选了药理学活性化合物库（LOPAC）小分子库，以寻找抑制真菌生长的化合物，并确定了一组化合物的 IC 值。基于这些发现，我们测试了一小部分这些药物，以验证筛选结果，并测试氟康唑联合治疗方案与单独使用氟康唑相比在小鼠模型中的效果。我们观察到，与单独使用氟康唑相比，他莫昔芬：氟康唑和舍曲林：氟康唑的联合治疗显著降低了肺部活真菌的负担，并且我们观察到传播减少或不存在。这些结果表明，他莫昔芬和舍曲林可能被重新用作治疗这种重要真菌病的辅助药物。
开发新药，特别是针对区域性孤儿病（如山谷热）的新药，是一项缓慢且昂贵的工作。然而，有大量已获 FDA 批准的药物可用于重新利用，为改善治疗提供了一种更经济、更快捷的方法。那些具有抗真菌特性的现有化合物可以相对容易地成为新的治疗方法：这对需要替代治疗的患者来说是一个相当大的优势。尽管仍有许多任务需要完成，但我们对潜在候选药物的全面筛选已经揭示了有希望的组合，可以比单一药物开发途径更快地影响患者。
