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

对抗耐药烟曲霉和耳念珠菌感染的新型联合疗法的发现和功能表征

基本信息

批准号：
2399071
负责人：
金额：
--
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2399071
关键词：
Discovery functional characterisation novel combination

项目摘要

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.

侵袭性真菌感染如果不治疗是致命的，但我们治疗此类疾病的能力受到耐药真菌的出现的威胁。迅速采取行动对抗这一威胁至关重要，但临床上可用的抗真菌药物很少，新药的发现和验证需要多年的时间才能完成。传统的抗真菌治疗方法一般集中在单独使用单一的抗真菌药物。然而，我们的团队最近优化了药物组合，这些药物明显提高了患者的存活率，并防止了隐球菌性脑膜炎的耐药性发展。因此，这项研究的目的是寻找对另外两种关键的耐药真菌：烟曲霉和金黄色念珠菌显示出巨大治疗前景的抗真菌药物组合。将对促进这些联合疗法抗真菌效力的潜在机制进行表征，评估突破耐药性的频率，并测试对其他致病真菌的活性光谱。我们研究计划的核心部分包括在感染的实验模型中验证有前景的组合疗法，以及对已经在临床使用的抗真菌药物进行分析，以期加速将有前景的疗法转化为临床。