Discovery and functional characterisation of novel combination therapies to combat drug-resistant Aspergillus fumigatus and Candida auris infections

侵袭性真菌感染如果不治疗是致命的，但我们治疗这类疾病的能力受到耐药真菌出现的威胁。迅速采取行动应对这一威胁至关重要，但可供临床使用的抗真菌药物很少，新药的发现和验证需要多年才能完成。传统的抗真菌治疗方法通常集中于使用分离的单一抗真菌药物。然而，我们的团队最近优化了药物组合，明显提高了隐球菌脑膜炎患者的生存率，并防止了耐药性的发展。因此，本研究的目的是鉴定抗真菌药物的组合，这些药物对另外两种至关重要的耐药真菌：烟曲霉和假丝酵母具有很大的治疗前景。将描述促进这些组合疗法抗真菌效力的潜在机制，评估突破性耐药性的频率，并测试对其他致病真菌的活性谱。我们研究计划的核心内容包括在感染实验模型中验证有希望的组合疗法，以及分析已经在临床使用的抗真菌药物，以期加速有希望的疗法转化为临床。

Invasive fungal infections are fatal if not treated, but our ability to treat such diseases is threatened by the emergence of drug-resistant fungi. It is critical to act quickly to combat this threat, and yet very few antifungal drugs are available for clinical use, and the discovery and validation of novel drugs takes many years to accomplish. Conventional approaches to antifungal therapy generally focus on using single antifungal drugs in isolation. However, our team has recently optimized combinations of drugs that demonstrably improve patient survival and prevent the development of resistance in cryptococcal meningitis. Therefore, the aim of this research is to identify combinations of antifungal agents that show great therapeutic promise against two other critically important drug-resistant fungi: Aspergillus fumigatus and Candida auris. The underlying mechanisms that promote the antifungal potency of these combinatorial therapies will be characterised, the frequency of breakthrough drug resistance assessed and the spectrum of activity against other disease-causing fungi will be tested. Central components of our research plan include the validation of promising combinatorial therapies in experimental models of infection, and the analysis of antifungal drugs already in clinical use, with a view to accelerating the translation of promising therapies into the clinic.