Bacterial partners as a mode of fungal resistance to antimicrobial compounds

项目摘要 微生物群落的种类组成决定了它们对人类健康的影响以及 环境，但我们对微生物群落如何形成的了解非常有限。一个主要的驱动力 这种成分是微生物之间的竞争，通过天然产生的抗菌剂进行调节。 化合物，这有助于塑造哪些微生物被包括在或排除在群落之外。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菌化合物很敏感。 对于真菌来说尤其如此，它们特别容易受到多种有毒抗真菌药物的攻击 微生物群落中产生的化合物。尽管如此，真菌在寄主相关的 植物、动物和人类的微生物群落。为了解释这种敏感的生物是如何获得 获得抗菌剂充满的空间，我的实验室发现了一类微生物相互作用 对抗微生物化合物有抵抗力的社区成员将保护扩展到身体 有关联的真菌伙伴。这样的细菌伙伴扮演着“毒素海绵”的角色，隔离天然的抗菌剂 化合物，除了提供对临床上用于抗真菌的一线抗真菌药物的保护 病原体。细菌伙伴保护其宿主真菌的发现提供了一条未被研究的途径 可用于A)预测微生物群落的形成和B)解剖新的机制 对抗真菌药物的抗药性，即抗药性源于细菌伙伴。 我的实验室致力于开发基于这种共生的模型系统，利用共同隔离的 真菌和细菌配对。这种真菌，哈里杜斯特曲霉，被发现与一种新的 我们将细菌命名为Paraburkholderia edwinii。我们已经使这种细菌在基因上易于驯服，并正在 努力对这种真菌做同样的事情。我们感兴趣的是发现工作机制 三个层面的保护。首先，在细菌的层面上，我们正在描述细菌是如何 对抗真菌化合物进行加工和解毒。第二，在细菌-真菌界面的层面上，我们 有兴趣了解真菌应激信号是如何传递给细菌以激活 保护响应。最后，在细菌-真菌混合共生菌的水平上，我们重点研究了 了解抗真菌药物如何通过真菌菌丝结构流向细菌 在药物解毒发生的地方形成的聚集体。除了涉及到的机制之外， 配对，我们的目标是从临床样本中共同分离细菌-真菌对，以确定哪些细菌成员 微生物群落为相关真菌以及哪些类别的抗真菌化合物提供了安全的避风港 这样的伙伴关系可以抵御。

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.