ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS

细胞壁完整性在新型隐球菌棘白菌素抗性中的作用

• 批准号: 10626232
• 负责人: Maureen J Donlin
• 金额: $ 36.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626232
• 关键词: ROLE; CELL; WALL; INTEGRITY; ECHINOCANDIN

Cryptococcus neoformans is a pathogenic fungus that is found world-wide and causes meningioencephalitis, particularly in immunocompromised individuals. It is invariably fatal unless treated, and the current antifungals are inadequate to effectively cure this disease, due to inherent toxicities, the inability to kill the fungus and prevent relapse, or innate resistance to the class of antifungals. Recent studies have indicated that there are over 1,000,000 new cases of cryptococcosis in the world each year, which results in over 600,000 deaths. New agents to treat Cryptococcus are needed, and the fungal cell wall is an attractive target, since it is unique to fungi and absent in humans. Echinocandins are a class of antifungals that target glucan synthesis in the cell wall. Cryptococcus is naturally resistant to the echinocandins. We have shown that disruption of the cell wall integrity (CWI) signaling pathway causes Cryptococcus to become highly sensitive to echinocandins, and identified candidate transcription factors that may play a role in echinocandin resistance. This pathway is the major pathway that impacts cell wall and is dependent on protein kinase C (Pkc1). The CWI/PKC1 pathway plays a key role in response to heat shock, oxidative and nitrosative stress, and cell wall inhibitors. Our preliminary data suggests that this pathway is part of a highly connected network that controls cell wall biosynthesis, repair and remodeling. The major goal of this project is to define the mechanism(s) by which cell wall integrity is maintained in response to specific cell wall inhibitors, including echinocandins and to identify potential gene targets for antifungals with synergy to echinocandins. There are three specific aims: In the first aim, we will define the role of the cell wall integrity pathway in echinocandin resistance using genomic and network analysis approaches. In the second aim, we will identify the genes essential to cell wall integrity and that contribute to echinocandin resistance by screening large deletion sets for specific phenotypes. In the third aim, we will assess the functional interactions of the cell wall integrity components. In this highly collaborative project, we propose to use our complementary expertise to integrate genetic, phenotypic and biochemical data to identify and characterize the network of interactions governing cell wall homeostasis in C. neoformans. This will significantly advance our understanding of cell wall maintenance and remodeling in a human pathogen and will provide multiple targets for designing specific antifungal drugs that are less likely to be toxic in mammals.

新型隐球菌是一种在世界范围内发现的致病真菌，可导致 脑膜脑炎，尤其是免疫功能低下的个体。它总是致命的，除非 治疗，目前的抗真菌药物不足以有效治愈这种疾病，因为 固有毒性，无法杀死真菌并防止复发，或对真菌有先天抵抗力 一类抗真菌药。最近的研究表明，有超过 1,000,000 例新病例 全世界每年都有隐球菌病，导致超过 60 万人死亡。新代理到 需要治疗隐球菌，而真菌细胞壁是一个有吸引力的目标，因为它是独特的 存在于真菌中，而存在于人类中。棘白菌素是一类针对葡聚糖的抗真菌药 在细胞壁中合成。隐球菌对棘白菌素具有天然抵抗力。我们有 研究表明，细胞壁完整性 (CWI) 信号通路的破坏会导致隐球菌 对棘白菌素变得高度敏感，并确定了候选转录因子 可能在棘白菌素耐药性中发挥作用。该途径是影响细胞的主要途径 壁并依赖于蛋白激酶 C (Pkc1)。 CWI/PKC1 通路在 对热休克、氧化和亚硝化应激以及细胞壁抑制剂的反应。我们的初步 数据表明该通路是控制细胞壁的高度连接网络的一部分 生物合成、修复和重塑。该项目的主要目标是定义 响应特定细胞壁而维持细胞壁完整性的机制 抑制剂，包括棘白菌素，并确定抗真菌药物的潜在基因靶点 与棘白菌素有协同作用。有三个具体目标：在第一个目标中，我们将定义角色 使用基因组和网络分析研究棘白菌素抗性中的细胞壁完整性途径 接近。在第二个目标中，我们将确定对细胞壁完整性至关重要的基因，并且 通过筛选特定表型的大缺失集来促进棘白菌素耐药性。 在第三个目标中，我们将评估细胞壁完整性成分的功能相互作用。 在这个高度协作的项目中，我们建议利用我们互补的专业知识来整合 遗传、表型和生化数据来识别和表征相互作用网络 控制新型隐球菌的细胞壁稳态。这将显着推进我们的 了解人类病原体细胞壁的维持和重塑，并将提供 设计不太可能有毒的特定抗真菌药物的多个目标 哺乳动物。

项目成果

Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans.

• DOI: 10.1021/acsomega.1c00273
• 发表时间: 2021-03-30
• 期刊: ACS omega
• 影响因子: 4.1
• 作者: Lin J;Zangi M;Kumar TVNH;Shakar Reddy M;Reddy LVR;Sadhukhan SK;Bradley DP;Moreira-Walsh B;Edwards TC;O'Dea AT;Tavis JE;Meyers MJ;Donlin MJ
• 通讯作者: Donlin MJ

Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii.

发现 5-Nitro-6-thiocyanatopyrimidines 作为新型隐球菌和格特隐球菌的抑制剂。

• DOI: 10.1021/acsmedchemlett.1c00038
• 发表时间: 2021
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Donlin,MaureenJ;Lane,ThomasR;Riabova,Olga;Lepioshkin,Alexander;Xu,Evan;Lin,Jeffrey;Makarov,Vadim;Ekins,Sean
• 通讯作者: Ekins,Sean

Membrane Integrity Contributes to Resistance of Cryptococcus neoformans to the Cell Wall Inhibitor Caspofungin.

• DOI: 10.1128/msphere.00134-22
• 发表时间: 2022-08-31
• 期刊: mSphere
• 影响因子: 4.8