CAREER: Rare Sugar Activation and Incorporation into Bacterial Glycan Polymers

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With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Tania Lupoli from New York University will investigate the synthesis and recognition of sugars unique to bacterial cell surfaces. Almost all bacteria contain polymers composed of sugars, called polysaccharides, that extend from their cell surfaces. Many bacterial surface polysaccharides contain rare sugars, which are bacteria-specific monosaccharides that are absent in mammals, including humans. While scientists recognize that rare sugars are important for mediating interactions between bacteria and their environments, there is still incomplete understanding of how rare sugar-containing polymers are assembled and how these enable survival in hosts during infection. The proposed experiments aim to develop chemical approaches to study enzymes that recognize rare sugars, with the goal of providing chemical tools to analyze bacterial interactions with their environments. This work will enable graduate students to obtain training in synthetic chemistry, biochemistry and microbiology. This project will also be integrated into educational outreach programs on infectious disease, bacterial survival and antibiotic design to inspire future scientists.This research project seeks to develop routes to nucleotide rare sugars, and to quantitatively characterize their interactions with glycosyltransferase enzymes that assemble bacterial surface polysaccharides. Rare bacterial sugars are over-represented in 6-deoxysugars, which lack the canonical hydroxyl group found on C6 of the hexose ring, and are typically L- as opposed to D-isomers. This proposal seeks to develop reagents to decipher the molecular consequences of installing sugars with uncommon stereochemistry that lack a 6-hydroxyl group into the cell surface of bacteria, with a focus on Gram-negative bacteria. Robust synthetic and chemoenzymatic routes to activated rare sugar substrates will be developed. The mechanism and catalytic sites of rare sugar-utilizing glycosyltransferases will be determined using detailed kinetic and mutagenesis studies. This work is expected to help establish molecular rules for recognition of 6-deoxysugars by bacterial glycosyltransferases that are currently uncharacterized.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.