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

背景人类真菌病原体是当前威胁人类健康的全球性疾病。念珠菌是代表人类最常见的真菌病原体的酵母菌，有几个物种很容易在医疗植入设备上形成生物膜，促进脆弱患者的感染。形成生物被膜的两个例子是白色念珠菌和金黄色葡萄球菌，白色念珠菌是医院获得性血液感染的第四大常见原因，金黄色念珠菌是一种高度耐药的物种，正在临床上迅速蔓延。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问题。古尔莱实验室的研究表明，线粒体呼吸链是一个弱点，可以作为新的抗真菌靶点。摩尔实验室开发了一个新型小分子文库，专门针对念珠菌呼吸系统的组件。学生团队将在药物设计(苏塞克斯的摩尔)、真菌细胞生物学(肯特郡的古尔莱)和全球医疗植入设备制造商(史密斯医疗公司)之间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。项目的目标学生的重点将是充分描述一系列新型真菌特异性呼吸抑制剂在防止医用级材料上形成生物膜的有效性，这些材料用于制造医疗植入物。这将使用古尔利和摩尔实验室内的临床相关模型和尖端实验技术来实现。在对抑制剂库进行硅学和生物化学评估后，将测试最有效的药物防止念珠菌生物被膜生长的能力。进一步的实验将结合细胞生物学、遗传学和基因组学方法来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.