Understanding Drug Resistance in Human Fungal Pathogens

耐药病原体的出现是一个日益严重的问题，因为它削弱了我们治疗常见感染的能力。尤其令人担忧的是，当真菌病原体对药物不再有反应时，抗真菌药物耐药性在全球范围内的蔓延。真菌病原体对动物、植物和生态系统健康构成威胁。事实上，真菌疾病每年造成约150万人死亡。致病真菌也对粮食安全构成全球性威胁，因为它们可以感染植物和作物，真菌感染正在推动南海岸生物科学博士培训伙伴关系（SoCoBio DTP）的灭绝电子邮件：socobio@soton.ac.uk网站：www.southcoastbiosciencesdtpseveral动物群体，包括蝙蝠、两栖动物和爬行动物。本项目旨在了解人类最常见的真菌病原体白色念珠菌的抗真菌耐药机制。白色念珠菌通常生活在人体中，不会造成任何伤害。然而，白色念珠菌可以在免疫功能低下的个体中引起危及生命的感染，例如正在接受化疗的癌症患者。只有三种有效的抗真菌药物可以治疗白色念珠菌感染，耐药性的出现严重阻碍了我们的治疗选择。蛋白质是包括真菌病原体在内的所有生物的主要功能分子。蛋白质可以在翻译后修饰（PTM）过程中进行化学修饰。PTMs调节蛋白质的功能、定位和活性。Buscaino实验室最近发现SUMOylation是调节白色念珠菌抗真菌耐药性的关键ptm1。事实上，缺少关键SUMO酶的白色念珠菌菌株通过积累特定的基因组重排而对抗真菌药物产生耐药性。该博士项目结合了我们在真菌遗传学，基因组学（Buscaino），定量蛋白质组学和生物信息学（Giamas）方面的专业知识，揭示了白色念珠菌蛋白SUMOylation如何以及为什么导致耐药性，以及sumomoylation机制如何调节白色念珠菌蛋白质组对抗真菌药物的反应。

The emergence of drug-resistant pathogens is an increasing problem as itdiminishes our ability to treat common infections. Especially alarming is theglobal spread of antifungal drug resistance occurring when fungal pathogensno longer respond to drugs.Fungal pathogens are a threat to animal, plant and ecosystem health.Indeed, fungal diseases cause ~ 1.5 million human death annually.Pathogenic fungi are also a worldwide threat to food security, as they caninfect plants and crops, and fungal infections are driving the extinction ofSouth Coast Biosciences Doctoral Training Partnership (SoCoBio DTP)Email: socobio@soton.ac.uk Website: www.southcoastbiosciencesdtpseveral animal groups, including bats, amphibians and reptiles.This project aims to understand the mechanisms of antifungal drugresistance in Candida albicans, the most common human fungal pathogen.C. albicans commonly live in the human body without causing any harm.However, C. albicans can cause life-threatening infections inimmunocompromised individuals such as cancer patients undergoingchemotherapy treatments. There are only three types of effective antifungaldrugs to treat C. albicans infection, and the emergence of drug resistanceseverely hinders our therapeutic options.Proteins are the primary functional molecules in all living organisms,including fungal pathogens. Proteins can be chemically modified in a processknown as Post-Translation Modification (PTM). PTMs modulate thefunction, localisation and activity of proteins.The Buscaino lab has recently identified SUMOylation as a key PTMregulating C. albicans antifungal drug resistance. Indeed, C. albicans strainslacking key SUMO enzymes develop resistance to antifungal drugs byaccumulating specific genomic rearrangements. This PhD project combinesour expertise in fungal genetics, genomics (Buscaino), quantitativeproteomics and bioinformatics (Giamas) to unveil how and why C. albicansprotein SUMOylation leads to drug resistance and how the SUMOylationmachinery regulates the C. albicans proteome in response to antifungaldrugs.