School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia.
School of Science, Royal Melbourne Institute of Technology, Melbourne, Victoria, Australia.
mSphere. 2024 Jun 25;9(6):e0024824. doi: 10.1128/msphere.00248-24. Epub 2024 Jun 5.
Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As current treatment options are limited, recent research has explored drug synergy with azoles for dermatophytoses. Bisphosphonates, which are approved to treat osteoporosis, can synergistically enhance the activity of azoles in diverse yeast pathogens but their activity has not been explored in dermatophytes or other molds. Market bisphosphonates risedronate, alendronate, and zoledronate (ZOL) were evaluated for antifungal efficacy and synergy with three azole antifungals: fluconazole (FLC), itraconazole (ITR), and ketoconazole (KET). ZOL was the most active bisphosphonate tested, displaying moderate activity against nine dermatophyte species (MIC range 64-256 µg/mL), and was synergistic with KET in eight of these species. ZOL was also able to synergistically improve the anti-biofilm activity of KET and combining KET and ZOL prevented the development of antifungal resistance. Rescue assays in revealed that the inhibitory effects of ZOL alone and in combination with KET were due to the inhibition of squalene synthesis. Fluorescence microscopy using membrane- and ROS-sensitive probes demonstrated that ZOL and KET:ZOL compromised membrane structure and induced oxidative stress. Antifungal activity and synergy between bisphosphonates and azoles were also observed in other clinically relevant molds, including species of and . These findings indicate that repurposing bisphosphonates as antifungals is a promising strategy for revitalising certain azoles as topical antifungals, and that this combination could be fast-tracked for investigation in clinical trials.
Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.
皮肤、毛发和指甲的浅表真菌感染是最常见的人类真菌病，许多感染对治疗有抗性。由于目前的治疗选择有限，最近的研究探索了唑类药物治疗皮肤真菌病的药物协同作用。双膦酸盐类药物已被批准用于治疗骨质疏松症，可协同增强多种酵母病原体中唑类药物的活性，但尚未在皮肤真菌或其他霉菌中研究其活性。对市场上的双膦酸盐类药物利塞膦酸钠、阿仑膦酸钠和唑来膦酸（zoledronate，ZOL）进行了抗真菌功效和与三种唑类抗真菌药（氟康唑（fluconazole，FLC）、伊曲康唑（itraconazole，ITR）和酮康唑（ketoconazole，KET））协同作用的评估。ZOL 是测试过的最有效的双膦酸盐类药物，对九种皮肤真菌具有中度活性（MIC 范围为 64-256μg/ml），并与其中八种皮肤真菌的 KET 具有协同作用。ZOL 还能够协同提高 KET 的抗生物膜活性，并且联合使用 KET 和 ZOL 可防止抗真菌耐药性的发展。揭示，ZOL 单独和与 KET 联合使用的抑制作用是由于鲨烯合成的抑制。使用膜和 ROS 敏感探针的荧光显微镜显示，ZOL 和 KET：ZOL 损害了膜结构并诱导了氧化应激。在其他临床相关霉菌中也观察到双膦酸盐类药物和唑类药物之间的抗真菌活性和协同作用，包括和属的某些物种。这些发现表明，将双膦酸盐类药物重新用作抗真菌药物是重新激活某些唑类药物作为局部抗真菌药物的有前途的策略，并且可以快速追踪该组合进行临床试验。
皮肤、毛发和指甲的真菌感染，通常统称为“tineas”，是全球最常见的传染病。这些感染是由真菌属皮肤癣菌引起的，通常是浅表性的，但在某些情况下可能会变得具有攻击性。它们也很难解决，有效的治疗方法很少，而且耐药性水平不断上升。在这里，我们报告了一种潜在的新治疗方法，将唑类抗真菌药物与双膦酸盐类药物联合使用。双膦酸盐类药物已被批准用于治疗低骨密度疾病，在真菌中，它们抑制细胞膜的生物合成，而细胞膜也是唑类药物的靶标。联合使用在各种皮肤癣菌中具有协同作用，并防止了耐药性的发展。我们将研究扩展到可引起侵袭性疾病的霉菌，发现一些有问题的物种存在协同作用。我们建议将双膦酸盐类药物重新用作治疗癣的协同药物，并且可以快速追踪该组合用于临床治疗。
