UC Santa Barbara

Natural products, or secondary metabolites, are small molecules produced primarily by bacteria, fungi, and plants. Their chemical diversity has conferred many useful bioactivities, such as antibacterial, antifungal, cholesterol-lowering, and immunosuppressant. In addition to their value as medicinal drugs, these molecules also serve important ecological roles in their native environments, by mediating interactions between microorganisms. Natural products are crucial to future microbiome engineering efforts for their natural ability to modulate microbial communities. The digestive tracts of large herbivores, including the rumen, harbor complex microbial communities, consisting of fungi, bacteria, protozoa, and methanogenic archaea. This vast reservoir of chemical diversity is almost completely untapped with regards to the discovery of natural products. These microbiomes are of interest both for their potential to yield new drug candidates and as a microbial platform for chemical production from renewable feedstocks. In this work, we explore the biosynthetic potential of anaerobic fungi native to the digestive tracts of herbivores to synthesize natural products. The genomes, transcriptomes, proteomes, and metabolomes of anaerobic fungi reveal that these underexplored fungi synthesize novel natural products, some of which are used to compete with rumen bacteria. Groundbreaking dual transcriptomics of rumen fungi co-cultured with rumen bacteria provides evidence that the relationship between these two organisms is antagonistic and that the presence of bacteria stimulates the expression of biosynthetic genes encoding enzymes that synthesize potential antibiotics. By sequencing the active genes of microbiomes inoculated from a source microbiome (goat fecal pellet), we demonstrated that the bacterial and fungal biosynthetic genes of natural products were active in sequential cultures passaged in vitro. We found that fungal biosynthetic genes were upregulated at later generations of batch passaging. This finding revealed that the expression of fungal biosynthetic genes is dynamic and suggested that natural products may function in the stability of the microbial community. Overall this dissertation points to the potential of natural products sourced from the rumen as drug candidates, as well as their importance in future microbiome engineering efforts.