Research

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Much like human beings, microbes often live in diverse communities interacting with both collaborators and competitors. Small molecule natural products mediate a significant portion of these interactions. As expected, the more complex a microbial community is, the richer its small molecule chemical arsenal becomes. This phenomenon has been observed in the complex microbiomes of marine invertebrates, terrestrial soils, human gut, and the plant rhizosphere, among others. Our ongoing efforts towards understanding these interactions will not only explain fundamentals of basic biology in these systems, but will also supply a suite of biologically active small molecules that can be developed as therapeutic agents.

Our research interests are mainly to study the chemical and biological interactions within complex microbial communities (microbe-microbe interactions) and between microbial communities and their multicellular hosts (microbe-host interactions). In addition, the Donia lab has a special interest in the uncultivable microbial components of complex communities, which have eluded research attempts for decades despite their abundance and clear importance. Recent advances in the fields of metagenomics and single-cell genomics have allowed access to the genetic information of some of these unculturable microbes, while functional studies remain challenging. We aim to develop the necessary computational and experimental tools to functionally study the interactions mediated by uncultivable members of complex microbiomes, using an integrated multi “omics” approach, including metagenomics, metabolomics and metatranscriptomics. The Donia Lab functions at the intersection between multiple disciplines: microbiology, molecular biology, biochemistry, pharmacology, small molecule chemistry and biosynthesis, metagenomics, and computational biology, aiming to answer basic biological questions and to develop new therapeutics.

 

 

 

Small-molecule-mediated interactions in the human microbiome

With respect to the human body and its microbial inhabitants (the human microbiome), small-molecule-mediated interactions can define the difference between commensals and pathogens, and thus between health and disease states. We are interested in studying these interactions at three main levels: a) identifying the chemical repertoire of the human microbiome; b) characterizing the biological activities and functional roles of the identified molecules in mediating microbiome-host interactions in health and disease states; and finally c) using this knowledge to aid the diagnosis and treatment of human diseases via microbiome-targeted therapies.

 

Small-molecule-mediated interactions in marine defensive symbioses

In the case of marine organisms (e.g., sponges, tunicates, mollusks, algae) and their symbionts, small-molecule-mediated interactions can provide the host with indispensable means of chemical defense, allowing it to survive in a predator-rich environment. We characterize these interactions by first determining the true microbial producers of the defensive molecules and the molecular mechanisms of their production, then we study the evolution of the symbiosis in light of the production of these molecules, and finally, we study the ecological consequences of their production for all interacting partners.

 

 

 

 

Microbiome-derived metabolism of administered drugs

In addition to the de novo production of small molecules, the human gut microbiome encodes a large repertoire of biochemical enzymes that can metabolize exogenous small molecules – whether they are derived from the human host, or from dietary or therapeutic sources. This concept has been explored for decades by using single isolates of the human microbiome against a common set of human-, drug-, or diet-derived chemicals, but has not been explored systematically. We aim to expand this area of research by developing high-throughout, unbiased approaches for defining the space of biochemical transformations that can be exerted by the collective human gut microbiome against a wide variety of chemicals, and the pharmacological consequences of these transformations.

 

Illustration by Janie Kim

 

Princeton