Revealing the Cell Wall Organization of Fungal Pathogens and Structural Responses to Antifungal Drugs Using Cellular Solid-State NMR

使用细胞固态核磁共振揭示真菌病原体的细胞壁组织和抗真菌药物的结构反应

基本信息

  • 批准号:
    10566511
  • 负责人:
  • 金额:
    $ 39.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-10 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary Invasive fungal infection has high occurrence and mortality among immunocompromised patients. Most of the currently available antifungal agents targeting the cell membrane have limited efficacy, relatively high toxicity, and an observed increase in drug resistance. The cell wall of fungal pathogens is a promising target for antifungal drugs due to its absence in humans. Still, such efforts have been hindered by our inadequate knowledge of the cell wall organization. The long-term goal of our research is to understand the structures of cell walls of prevalent fungal pathogens at the molecular level to promote the development of wall- targeting therapeutics against infections. This project aims to develop solid-state nuclear magnetic resonance (ssNMR) technology that allows understanding the nanoscale remodeling of fungal cell wall structures involved in fungal virulence and drug resistance. The central hypothesis is that the fungal cell walls’ structural dynamics and mechanical properties are major factors contributing to virulence and drug resistance. This central hypothesis will be tested by three specific aims. We will interrogate the polymorphic structure of major structural polysaccharides and their supramolecular packing in the cell walls of three major fungal pathogens, including Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Second, we will determine the structural dynamics of the cell wall and the remodeling process of the biopolymer composite induced by antifungal echinocandins and nikkomycin that target, respectively, β- glucan and chitin, two of the major cell wall components. Third, we will examine cell wall structures of naturally occurring mutant strains of A. fumigatus and C. albicans showing modulated susceptibility to antifungal agents and the superbug Candida auris to identify the structural mechanisms underlying altered drug responses. We will pursue these aims by establishing an innovative approach that combines ssNMR and dynamic nuclear polarization (DNP) techniques to enable high-resolution and non-destructive characterization of intact and living fungal cells. The project is significant because it will identify the essential carbohydrate components and their structures or packing interfaces that serve as the potential targets for discovering novel antifungal compounds with broad spectrums and improved efficacy. Our efforts will yield a collection of structural diagrams of cell walls across three major fungal pathogens and their responses to antifungal agents and mutations. The research will define a new biophysical direction bridging the long- standing gap between biomedical observations of fungal phenotypes and the fundamental understanding of structures and interactions of biomolecules at atomic levels. The methodology established here will also permit the high-resolution assessment of structural effects of antifungal agents that are available or being developed, which will revolutionize antifungal drug design.
项目摘要 侵袭性真菌感染在免疫功能低下的患者中有很高的发生率和死亡率。大部分 目前可获得的靶向细胞膜的抗真菌剂具有有限的功效、相对高的抗真菌活性、或相对低的抗真菌活性 毒性和观察到的耐药性增加。真菌病原体的细胞壁是一个很有前途的靶点 抗真菌药物,因为它在人类中不存在。尽管如此,这种努力仍然受到我们的不足的阻碍, 细胞壁组织的知识。我们研究的长期目标是了解 细胞壁的流行真菌病原体在分子水平上,以促进壁的发展, 针对感染的靶向治疗剂。该项目旨在开发固态核磁 共振(ssNMR)技术,可以理解真菌细胞壁的纳米级重塑 真菌毒力和抗药性的结构。核心假设是真菌细胞 细胞壁的结构动力学和力学性质是影响毒力和药物毒性的主要因素 阻力这一核心假设将通过三个具体目标进行检验。我们会审问多形生物 主要结构多糖的结构和它们在三种主要的细胞壁中的超分子包装 真菌病原体,包括烟曲霉、白色念珠菌和新型隐球菌。 其次,我们将确定细胞壁的结构动力学和细胞壁的重塑过程。 抗真菌棘白菌素和尼可霉素诱导的生物聚合物复合物,分别靶向β- 葡聚糖和几丁质,两种主要的细胞壁成分。第三,我们将研究细胞壁结构, 天然存在的A.和C.白色念珠菌表现出对 抗真菌剂和超级细菌耳念珠菌,以确定改变的结构机制, 药物反应。我们将通过建立一种结合ssNMR的创新方法来实现这些目标 和动态核极化(DNP)技术,以实现高分辨率和非破坏性 完整和活的真菌细胞的表征。该项目意义重大,因为它将确定 作为潜在目标的碳水化合物组分及其结构或包装界面 发现具有广谱和改进功效的新型抗真菌化合物。我们的努力将会产生成果 三种主要真菌病原体的细胞壁结构图及其对 抗真菌剂和突变。这项研究将确定一个新的生物物理学方向, 真菌表型的生物医学观察和对真菌的基本认识之间存在着巨大的差距。 生物分子在原子水平上的结构和相互作用。在此建立的方法也将 允许高分辨率评估可用或正在使用的抗真菌剂的结构效应 这将彻底改变抗真菌药物的设计。

项目成果

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