Four-stranded fungal fatality: Unveiling G-quadruplexes as future antifungal targets

四链真菌死亡：揭示 G-四链体作为未来抗真菌靶点

• 批准号: BB/Y005058/1
• 负责人: Stefan Bidula
• 金额: $ 56.99万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY005058%2F1
• 关键词: Four; stranded; fungal; fatality; Unveiling; Four; stranded; fungal; fatality; Unveiling

Fungal infections are a serious and underappreciated threat to food security, animal biodiversity, and human health.Fungi cause around 85% of all plant infections and the loss of important food crops such as rice, wheat, and maize. Some types of fungi also cause serious infections in wild and domesticated animals. Bats, bees, reptiles, and frogs are particularly at risk, with some species of frog already becoming extinct due to fungal infections. Recently, the World Health Organization compiled the first list of priority fungal pathogens that cause diseases in humans. Four fungal species were of critical priority to combat (Aspergillus fumigatus, Candida albicans, Candida auris, Cryptococcus neoformans) and account for most of the almost 2 million deaths in humans worldwide. These fungi cause life-threatening infections in people with weaker immune systems. These people include those undergoing treatments such as chemotherapy, carrying underlying infections such as the coronavirus, and patients receiving stem cell or organ transplants. In these patient groups, fungal infections can often have mortality rates exceeding 50%. This already serious issue is soon to become far more severe because the drugs we once used to treat fungal infections no longer work as effectively as they once did. This is because drug resistance has now emerged to the few effective drugs we have to treat life-threatening fungal infections. Therefore, it is now urgent that we try and find new ways to combat these fungal threats. Most people are familiar with the iconic DNA double-helix, but DNA can take many different forms. One such form is the G-quadruplex, an unusual DNA structure which stacks up like a bookcase. They have been shown to have vital roles in living organisms and can control important processes such as when genes are switched on or off or how an organism grows. We have recently discovered that drugs which interact with G-quadruplexes can kill disease-causing fungi. We must now find out why this happens and identify how G-quadruplexes control important biological processes in fungi. By clarifying the fundamental roles of G-quadruplexes and how they function in fungi, there is good potential to identify a completely new target for antifungal drug development. This understanding will increase our armoury against the emerging fungal threat and help us to protect food security, improve animal welfare, and preserve global health.

真菌感染是对粮食安全，动物生物多样性和人类健康的严重且被低估的威胁。Fungi导致所有植物感染的约85％，以及米饭，小麦和玉米等重要食品作物的丧失。某些类型的真菌还会引起野生和家养动物的严重感染。蝙蝠，蜜蜂，爬行动物和青蛙特别有风险，由于真菌感染，一些青蛙已经灭绝了。最近，世界卫生组织汇集了引起人类疾病的首个优先真菌病原体清单。四种真菌物种对战斗是至关重要的（烟草，白色念珠菌，念珠菌，念珠菌，新粘液虫），占全世界近200万人死亡的大部分死亡。这些真菌会导致免疫系统较弱的人威胁生命的感染。这些人包括接受化学疗法的那些人，携带诸如冠状病毒之类的潜在感染以及接受干细胞或器官移植的患者。在这些患者群体中，真菌感染通常可以使死亡率超过50％。这个已经很严重的问题很快就会变得更加严重，因为我们曾经用来治疗真菌感染的药物不再像以前那样有效。这是因为现在已经出现了耐药性的少数有效药物，我们必须治疗威胁生命的真菌感染。因此，现在迫切希望找到应对这些真菌威胁的新方法。大多数人都熟悉标志性的DNA双螺旋，但是DNA可以采取许多不同的形式。一种这样的形式就是G Quadruplex，这是一种异常的DNA结构，像书架一样堆叠起来。它们已被证明在活生物体中具有至关重要的作用，并且可以控制重要过程，例如何时打开或关闭基因或生物的生长方式。我们最近发现，与G-四链体相互作用的药物可以杀死引起疾病的真菌。现在，我们必须找出为什么会发生这种情况，并确定G Quadruplexes如何控制真菌中重要的生物学过程。通过阐明G四链体的基本作用及其在真菌中的作用，可以识别出抗真菌药物开发的全新目标的良好潜力。这种理解将增加我们对新兴的真菌威胁的军械库，并帮助我们保护粮食安全，改善动物福利并保护全球健康。