Next generation mitochondrial inhibitors - a new approach to prevent fungal biofilm formation on med

人类真菌病原体是当前对人类健康的全球性威胁。念珠菌是代表最常见的人类真菌病原体的酵母菌，有几种很容易在医疗植入装置上形成生物膜，促进易感患者的感染。生物膜形成念珠菌的两个例子是白色念珠菌，这是医院获得性血液感染的第四大常见原因，以及金黄色念珠菌，这是一种高度耐药的物种，正在迅速蔓延到整个临床领域。对现有抗真菌治疗的耐药性增加意味着迫切需要新的方法来解决真菌生物膜的生长。Gourlay实验室的研究表明，线粒体呼吸链是一个弱点，可以作为一种新的抗真菌靶点。摩尔实验室开发了一个新的小分子库，专门针对念珠菌呼吸系统的组成部分。该学生将在药物设计（Moore, Sussex），真菌细胞生物学（Gourlay, Kent）和全球医疗植入设备制造商（Smith medical Inc .）的领先专家的合作下评估这些下一代抑制剂。该项目是高度多学科的，可能会产生与行业相关的重大成果。该项目的重点将是全面描述一系列新型真菌特异性呼吸抑制剂在防止用于制造医疗植入物的医疗级材料上形成生物膜方面的有效性。这将在Gourlay和Moore实验室中使用临床相关模型和尖端实验技术来实现。随后在硅和生化评估抑制剂库最有效的将在他们的能力进行测试，以防止念珠菌物种的生物膜生长。进一步的实验将结合细胞生物学、遗传学和基因组学方法确定作用模式和分子基础。

Background Human fungal pathogens represent a current global threat to human health. Candida are yeasts that represent the most common human fungal pathogens and several species readily form biofilms on medical implant devices that promote infection in vulnerable patients. Two examples of biofilm forming Candida species are C. albicans, the fourth most commoncause of hospital acquired blood infections, and C. auris, which represents a highly drug resistant species that is rapidly spreading across the clinical landscape. An increase in resistance to available antifungal treatments means that there is an urgent need for new approaches to tackle fungal biofilm growth. Research from the Gourlay lab suggests that the mitochondrial respiratory chain is a point of weakness that can be exploited as a new anti-fungal target. The Moore lab has developed a library of novel small molecules that specifically target components of the Candida respiratory system. The studentship will evaluate these next generation inhibitors within a collaboration between leading experts in drug design (Moore, Sussex), fungal cell biology (Gourlay, Kent) and a global manufacturer of medical implant devices (Smith Medical Inc). The project is highly multi-disciplinary and likely to result in significant results of industrial relevance. Aims of project The focus of the studentship will be to fully characterise the effectiveness of a range of novel fungal specific respiratory inhibitors in preventing biofilm formation on medical grade materials used to manufacture medical implants. This will be achieved using clinically relevant models and cutting edge experimental techniques within the Gourlay and Moore laboratories. Following in silico and biochemical assessment of a library of inhibitors the most effective will be tested in their ability to prevent Candida species biofilm growth. Further experiments will determine the mode of action and molecular basis using a combination of cell biological, genetic and omic approaches.