Fungal Phospholipases: A Novel Drug Discovery Platform

侵袭性真菌感染是一个严重且不断升级的健康问题。它们会导致严重的疾病，死亡率很高，并且对卫生系统来说代价非常高昂。在免疫功能低下的患者中尤其如此，如血液恶性肿瘤、器官移植接受者和艾滋病患者。目前可用于治疗真菌感染的药物数量有限，通常不是非常有效，就是毒性很大。对这些药物产生抗药性的真菌菌株的发展也变得有问题。迫切需要通过确定真菌细胞中的新靶点和-或防止感染在人类宿主中传播的靶点来发现和开发有效地对抗真菌感染的新药。我们首次描述了一种酶，磷脂酶B(PLB1)，它是由医学上重要的真菌新生隐球菌分泌的，在这种真菌入侵人体组织的过程中起着重要的作用。它在真菌细胞膜的重塑过程中也很重要。这种酶与人的磷脂酶有很大的不同，是抗真菌药物的良好靶点。在这个项目中，我们的目标是合成和测试应该抑制PLB活性并通过这种方式阻止其有害影响的分子。我们将测试这些药物的效果，以确保它们不会干扰人类的酶系统。抑制性化合物也可以用来杀死真菌细胞，特别是如果与目前使用的治疗方法一起使用的话。具有新作用模式的新抗真菌药物的设计和开发代表着真菌疾病治疗方面的重大进步，并为每个受影响的患者节省约60000澳元(根据美国最近的一项研究估计)。

Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to these drugs is also becoming problematic. There is an urgent need to discover and develop new drugs effective against fungal infections through identifying new targets in the fungal cell and-or targets that prevent the spread of infection in the human host. We were the first to describe an enzyme, phospholipase B (PLB1), which is secreted by the medically important fungus, Cryptococcus neoformans, and is important in invasion of human tissue by the fungus. It is also important in remodelling of membranes in the fungal cell. This enzyme is sufficiently different from human phospholipases to be a good target for antifungal drugs. In this project, we aim to synthesise and test molecules which should inhibit the activity of PLB and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be used to kill the fungal cells, especially if administered together with currently used therapies. The design and development of new antifungal drugs with a novel mode of action represents a major advance in the treatment of fungal disease, and a saving of some A$60000 per affected patient (estimated from a recent US study).