Meshing Synthesis and Biosynthesis for KDO: A Key Plant and Bacterial Sugar

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KDO (2-keto-3-deoxy-D-manno-octulosonic acid) is an unusual 8-carbon acidic sugar that is essential for the growth of many pathogenic bacteria affecting plants and animals. For example, in Gram-negative bacteria such as Brucella, which causes severe infections in humans and lifestock KDO is a crucial part of the Lipid A-based lipopolysaccharides. KDO has also been discovered in plants and green algae, although its biological roles in these organisms are still unclear. The high cost of this sugar coupled with the challenge of making it by chemical synthesis has limited basic scientific studies of the synthetic chemistry of KDO, its biological roles, and the development of antibiotics based on inhibiting KDO-based pathways. This project aims to 1) optimize engineering efforts to obtain KDO in gram quantities from a bacterial source, 2) investigate chemical methods to link KDO to other structures, 3) explore protocols to use KDO building blocks in an automated solution-phase oligosaccharide synthesis platform to incorporate this sugar into larger bioactive structures, and 4) test the binding of KDO to a range of plant carbohydrate-binding proteins called lectins to discover potential binding partners of this pathogen-associated sugar. Broader Impact: This interdisciplinary project will broaden the participation of underrepresented groups by inclusion of students from underrepresented groups as participants in the proposed research and education activities; advance discovery and understanding while promoting teaching, training, and learning by inclusion of graduate and undergraduate students as participants and the encouragement of their participation at national and international scientific meetings; and develop the first fermentation-based production processes and new chemistry of an unusual sugar key to bacterial infectiousness of plants and animals to help unravel the infection processes and ultimately inhibit these infections.