Bacterial partners as a mode of fungal resistance to antimicrobial compounds

细菌伙伴作为真菌对抗菌化合物产生耐药性的一种模式

• 批准号: 10714362
• 负责人: Kurt M. Dahlstrom
• 金额: $ 36.84万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714362
• 关键词: Animals; Antifungal Agents; Antimicrobial Resistance; Aspergillus; Bacteria; Biological; Biological Models; Clinical; Communication; Communities; Drug Metabolic Detoxication; Drug usage; Environment; Exclusion; Health; Human; Infection; Knowledge; Mediating; Microbe; Names; Nature; Organism; Pharmaceutical Preparations; Plants; Play; Porifera; Process; Resistance; Sampling; Shapes; Signal Transduction; Stress; Structure; Symbiosis; Toxin; Treatment Failure; Work; antimicrobial; antimicrobial drug; fungus; host-associated microbial communities; interest; member; microbial community; microbial composition; microorganism interaction; natural antimicrobial; novel; pathogenic fungus; resistance mechanism; response

Project Summary The species composition of microbial communities determines the impact they have on human health and the environment, but we have a very limited understanding of how microbial communities form. A major driver of this composition is a competition among microbes that is mediated by naturally produced antimicrobial compounds, that help shape which microbes are included or excluded from the community. Notably, many key microbes found in these communities are sensitive to the natural antimicrobial compounds produced therein. This is especially true for fungi, which are particularly vulnerable to many classes of toxic antifungal compounds produced within microbial communities. Despite this, fungi play key roles in host-associated microbial communities for plants, animals, and humans. In order to explain how such sensitive organisms gain access to antimicrobial replete spaces, my lab discovered a class of microbial interactions whereby bacterial members of the community that are resistant to antimicrobial compounds extend protection to physically associated fungal partners. Such bacterial partners act as “toxin sponges,” sequestering natural antimicrobial compounds, in addition to providing protection against frontline antifungal drugs used clinically against fungal pathogens. The discovery of bacterial partners protecting their host fungi provides an unstudied avenue that can be applied to A) predicting how microbial communities form and B) dissecting new mechanisms of resistance to antifungal drugs whereby resistance originates from a bacterial partner. My lab focuses on developing a model system based on this type of symbiosis, making use of a co-isolated fungal-bacterial pairing. The fungus, Aspergillus calidoustus, was found physically associated with a novel bacterium we named Paraburkholderia edwinii. We have rendered the bacterium genetically tractable and are working to do the same with the fungus. We are interested in discovering the mechanisms at work for protection on three levels. First, at the level of the bacterium, we are characterizing how the bacterium processes and detoxifies antifungal compounds. Second, at the level of the bacterial-fungal interface, we are interested in understanding how signals of fungal stress are communicated to the bacterium to activate the protection response. Finally, at the level of the mixed bacterial-fungal co-colony, we are focused on understanding how antifungal drug flow is manipulated through the fungal mycelial structure to bacterial aggregates that form within where detoxification of the drugs occurs. Beyond the mechanisms involved in this pairing, we aim to co-isolate bacterial-fungal pairs from clinical samples to identify which bacterial members of microbial communities provide safe harbor for associated fungi, and to what classes of antifungal compounds such partnerships can defend against.

项目摘要 微生物群落的物种组成决定了它们对人类健康的影响， 环境，但我们对微生物群落如何形成的了解非常有限。的主要驱动力 这种组合物是微生物之间的竞争， 化合物，帮助塑造哪些微生物被包括或排除在社区之外。值得注意的是，许多关键 在这些群落中发现的微生物对其中产生的天然抗微生物化合物敏感。 对于真菌来说尤其如此，它们特别容易受到许多种类的有毒抗真菌药物的影响。 微生物群落中产生的化合物。尽管如此，真菌在宿主相关的 微生物群落对植物、动物和人类的影响。为了解释这些敏感的生物体是如何 进入充满抗菌剂的空间，我的实验室发现了一类微生物的相互作用， 对抗菌化合物有耐药性的社区成员将保护范围扩大到身体上， 相关真菌伴侣。这种细菌伴侣就像“毒素海绵”， 化合物，除了提供对临床上用于对抗真菌的一线抗真菌药物的保护外， 病原体细菌伴侣保护宿主真菌的发现提供了一种未经研究的途径， 可以应用于A）预测微生物群落如何形成和B）剖析微生物群落的新机制。 对抗真菌药物的抗性，其中抗性来源于细菌伴侣。 我的实验室专注于开发一个基于这种共生的模型系统，利用一个共同隔离的 真菌-细菌配对这种真菌，曲霉calidoustus，被发现与一本小说的物理联系 我们命名为副伯克霍尔德氏菌。我们已经使这种细菌在遗传上易于控制， 对真菌做同样的事情。我们感兴趣的是发现工作机制， 三个层次的保护。首先，在细菌的层面上，我们描述了细菌是如何 处理和解毒抗真菌化合物。其次，在细菌-真菌界面的水平上，我们 有兴趣了解真菌压力的信号是如何传达给细菌，以激活 保护响应。最后，在混合细菌-真菌共菌落的水平上， 了解抗真菌药物如何通过真菌菌丝体结构流向细菌 在药物解毒发生的地方形成的聚集体。除了这些机制之外， 配对，我们的目标是从临床样本中共分离细菌-真菌对，以确定哪些细菌成员 微生物群落为相关真菌提供了安全的港湾，以及哪些类别的抗真菌化合物 这样的伙伴关系可以抵御。