Li Cecilia, Lev Sophie, Saiardi Adolfo, Desmarini Desmarini, Sorrell Tania C, Djordjevic Julianne T
Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
J Fungi (Basel). 2016 Sep 6;2(3):24. doi: 10.3390/jof2030024.
Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. , the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1)-dependent pathway in comprising of sequentially-acting inositol polyphosphate kinases (IPK), which are involved in synthesizing inositol polyphosphates (IP). We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P) and pyrophosphate (PP) groups covalently attached at different positions. This review focuses on (1) the characterization of the Plc1/IPK pathway in ; (2) the identification of PP-IP₅ (IP₇) as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3) why IPK enzymes represent suitable candidates for drug development.
机会性真菌是全球发病和死亡的主要原因，尤其是在免疫功能低下的个体中。鉴于真菌和哺乳动物宿主细胞都是真核细胞，具有相似的组织结构和生理功能，开发新的治疗方法来对抗侵袭性真菌病具有挑战性。即使是针对独特真菌细胞特征的疗法也有局限性，而且耐药性正在出现。因此，迫切需要开发抗真菌药物的新方法。新生隐球菌是全球真菌性脑膜炎最常见的病因，是研究真菌致病性和推动药物发现的公认模型。我们最近在新生隐球菌中鉴定了一条依赖磷脂酶C（Plc1）的信号通路，该通路由依次作用的肌醇多磷酸激酶（IPK）组成，这些激酶参与合成肌醇多磷酸（IP）。我们还表明，该信号通路对真菌细胞功能和致病性至关重要。该信号通路的IP产物结构多样，每个产物都由一个肌醇环组成，磷酸（P）和焦磷酸（PP）基团共价连接在不同位置。本综述重点关注：（1）新生隐球菌中Plc1/IPK信号通路的特征；（2）在真菌感染小鼠模型中，鉴定PP-IP₅（IP₇）是对真菌健康和毒力最关键的IP种类；（3）为什么IPK酶是药物开发的合适候选对象。
