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|Title:||ELUCIDATING THE MECHANISMS UNDERLYING MICROBIAL INTERACTIONS IN THE HUMAN MICROBIOME AT THE MOLECULAR SCALE|
|Advisors:||Abou Donia, Mohamed S|
|Contributors:||Molecular Biology Department|
|Publisher:||Princeton, NJ : Princeton University|
|Abstract:||The human microbiome is a complex ecosystem of microbial life that is deeply involved in several aspects of human health. However, the mechanisms by which the microbiome impacts human health remains mostly uncharacterized. To understand these mechanisms at a molecular level, a focus will be given microbially derived small molecules, which are important mediators of microbial interactions. Herein will be detailed three different research projects that aim to understand the molecules and mechanisms behind important interactions in the human microbiome.In the first project, a relatively new family of antimicrobial peptides, distinguished by a specific modification enzyme called a radical SAM (rSAM), are identified in the gut microbiome. From this search, we selected previously uncharacterized biosynthetic gene clusters (BGCs) for expression and purification. These molecules represent an exciting class of molecules which may have implications for microbial competition occurring in the human gut. In the second project, we utilize whole genome sequencing to characterize three bacterial species that compose a currently marketed probiotic treatment. Next, analysis of the probiotic bacteria in the context of an ex vivo microbiome culture is utilized to identify the impact of the probiotic bacteria in the context of a microbial community. These results will aid in understanding the complex interactions between probiotics and the gut microbiome on a molecular scale. In the last project, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose, resulting in its inactivation. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases (Maks) are extremely specific for acarbose, that they provide their harboring organism with a protective advantage against acarbose’s activity, and that they are widespread in the microbiome of numerous human populations. These newly characterized enzymes have the potential to shape both microbial interactions as well as impacting the host in diabetic treatment. Together these three projects help further our understanding of the molecules and mechanisms by which the microbes in our body compete with one another and ultimately even impact human health.|
|Alternate format:||The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu|
|Type of Material:||Academic dissertations (Ph.D.)|
|Appears in Collections:||Molecular Biology|
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