Investigation of commensal bacteria-produced metabolites with activity towards mycobiota.

项目摘要 人类肠道支持复杂的微生物环境，包括细菌(或 微生物区系)和真菌(或真菌生物区系)成分。尽管这些生物中的每一个在引诱 肠道中的免疫激活和炎症以及它们引发全身感染的能力已经开始 被更大的科学界研究和欣赏，它们在物种之间的相互作用 胃肠道的背景仍然是一个代表性不足的研究领域。其化学基础是 这种相互作用对于合理设计胃肠道感染和疾病的治疗方案至关重要。 文学中完全未知的领域。这与地球上生机勃勃的田野形成了鲜明对比 海洋次生代谢物的结构测定和生物活性，在那里似乎源源不断的 真菌和细菌之间的生物合成天然产物和效应途径已被阐明。我们的 初步的核糖体16S测序数据显示，厌氧细菌的特定群落是 随着各种抗真菌药物的使用，以可重复的方式急剧增加。这一分析表明 细菌和真菌可能在肠道生态系统中占据类似的、竞争的生态位。照亮 细菌代谢产物影响真菌生物群的潜力，从而建立竞争优势， 我们开发了一个已知肠道代谢物的资料库，并对生理相关的抗真菌活性进行了筛选。 体外条件。这导致鉴定出两种细菌来源的代谢物，其活性为 真菌生物群中投机取巧的成员。因此，我们假设条件致病真菌在 肠道受到细菌代谢产物的抑制，这一机制受到肠道的刺激 真菌影响感染状态。除了揭示真菌-细菌相互作用的新机制外， 前所未有的小分子水平，这项拟议的研究结果将阐明潜在的新的 针对真菌病原体的策略。

Project Summary The human intestinal tract supports a complex microbial environment consisting of bacterial (or microbiota) and fungal (or mycobiota) constituents. Although the role of each of these organisms in eliciting immune activation and inflammation in the gut as well as their ability to initiate systemic infection has begun to be investigated and appreciated by the larger scientific community, their interspecies interactions within the context of the gastrointestinal tract remains an underrepresented area of research. The chemical basis for such interactions, critical for the rational design of treatments in gastrointestinal infection and disease, remain completely uncharted territory in the literature. This lies in stark contrast to the vibrant fields of terrestrial and marine secondary metabolite structural determination and bioactivity, where a seemingly endless stream of biosynthesized natural products and effector pathways have been elucidated between fungi and bacteria. Our preliminary ribosomal 16S sequencing data show that specific communities of anaerobic bacteria are drastically increased in a reproducible way with a variety of antifungal medications. This analysis indicates that bacteria and fungi may occupy a similar, competitive ecological niche within the gut ecosystem. To illuminate the potential for bacterial metabolites to influence the mycobiota, thereby establishing a competitive advantage, we developed a library of known gut metabolites and screened for antifungal activity at physiologically relevant conditions in vitro. This resulted in the identification of two metabolites of bacterial origin with activity towards opportunistic members of the mycobiota. We therefore hypothesize that opportunistic pathogenic fungi in the gut are held in check by bacterial metabolite production and that this mechanism is stimulated by intestinal fungi to impact infectious states. In addition to revealing novel mechanisms of fungal-bacterial interaction at an unprecedented small molecule level, the results of this proposed investigation will illuminate potential new strategies for targeting of fungal pathogens.