Improving detection and diagnosis of antimicrobial resistance in Aspergillus fumigatus

烟曲霉是一种普遍存在的霉菌，在环境中分解植物物质起着关键作用。然而，烟曲霉吸入后可引起一系列疾病，包括对具有某些免疫缺陷的人造成威胁生命的感染。我们可以用唑类药物治疗患者，但由于耐药性，这些药物的效果越来越差。耐药性通常不会在治疗期间产生，而是在感染建立之前就已经存在于真菌中。研究人员发现，这种真菌在含有唑类杀菌剂残留物的有机废物中生长时，会在环境中产生抗药性。抗药性是由真菌的DNA变化引起的。当真菌引起感染时，需要检测到这些，以便相应地调整治疗。一个主要问题是，很难确定患者是否患有耐药感染，因为目前的检测方法不是很好。与耐药性相关的DNA变化范围越来越大，这使问题更加恶化，事实上，20%的耐药真菌的DNA变化是未知的。在这项提议中，我们的目标是确认现有DNA变化的存在，并找到导致耐药性的新DNA变化，然后利用这些知识开发更好的诊断测试。我们还将改进一种筛选试验，使其能够检测对一种重要的新开发药物的耐药性。开发更好的诊断测试将使患者受益，将有助于确定患者感染耐药烟曲霉的频率，并提高对患者如何被感染的了解。

Aspergillus fumigatus is a ubiquitous mould that plays a critical role breaking down plant material in the environment. However, A. fumigatus may cause a range of diseases when inhaled, including life-threatening infections in humans with certain immune defects. We can treat patients with azole drugs, but increasingly these drugs have become less effective due to resistance. Resistance usually does not develop during therapy but is already present in the fungus before infection is established. Researchers have found that the fungus becomes resistant in the environment when it grows in organic waste containing residues of azole fungicides. Resistance is caused by DNA changes in the fungus. These need to be detected when the fungus causes an infection so treatment can be adjusted accordingly. A major problem is that it is very difficult to determine if a patient has a resistant infection because current tests are not very good. The problem is worsened by an increasing range of DNA changes associated with resistance, indeed for 20% of resistant fungi the DNA changes are unknown. In this proposal we aim to confirm the presence of existing DNA changes and find new DNA changes that cause resistance, and then use this knowledge to develop better diagnostic tests. We will also improve a screening test by enabling it to detect resistance against an important newly developed drug. The development of better diagnostic tests will benefit patients, will help establish how often patients are infected with resistant A. fumigatus, and improve understanding of how patients become infected.