Bacterial partners as a mode of fungal resistance to antimicrobial compounds

项目总结

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.