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

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威胁，但未得到充分重视。真菌导致约85%的植物感染和重要粮食作物（如水稻、小麦和玉米）的损失。某些类型的真菌也会在野生和家养动物中引起严重感染。蝙蝠、蜜蜂、爬行动物和青蛙尤其面临风险，一些青蛙物种已经因真菌感染而灭绝。最近，世界卫生组织编制了第一份导致人类疾病的优先真菌病原体清单。四种真菌物种是至关重要的优先打击（烟曲霉，白色念珠菌，耳念珠菌，新型隐球菌），并占全球近200万人死亡的大部分。这些真菌在免疫系统较弱的人中引起危及生命的感染。这些人包括接受化疗等治疗的人，携带冠状病毒等潜在感染的人，以及接受干细胞或器官移植的患者。在这些患者群体中，真菌感染的死亡率通常超过50%。这个已经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。这是因为耐药性已经出现在我们治疗危及生命的真菌感染的少数有效药物中。因此，我们现在迫切需要尝试寻找新的方法来对抗这些真菌威胁。大多数人都熟悉标志性的DNA双螺旋，但DNA可以采取许多不同的形式。其中一种形式是G-四链体，这是一种不寻常的DNA结构，像书架一样堆叠起来。它们已被证明在生物体中起着至关重要的作用，可以控制重要的过程，例如基因何时打开或关闭，或者生物体如何生长。我们最近发现，与G-四链体相互作用的药物可以杀死致病真菌。我们现在必须找出为什么会发生这种情况，并确定G-四链体如何控制真菌中的重要生物过程。通过阐明G-四链体的基本作用以及它们在真菌中的功能，有很好的潜力来确定一个全新的抗真菌药物开发靶点。这一认识将增加我们应对新出现的真菌威胁的武器库，并帮助我们保护粮食安全，改善动物福利，保护全球健康。