Bacteria are surrounded by a cell wall containing layers of peptidoglycan, the integrity of which is essential for bacterial survival. In the final stage of peptidoglycan biosynthesis, enzymes called transglycosylases catalyze the polymerization of a disaccharide pentapeptide building block to form the carbohydrate chains of peptidoglycan. Transglycosylases are believed to have tremendous potential as antibiotic targets, but there is no detailed structural or mechanistic information on any of them. The natural product moenomycin is proposed to kill bacterial cells by binding to bacterial transglycosylases but almost nothing is known about how it interacts with these enzymes. Because the chemistry and biology of bacterial transglycosylases is so poorly understood, scientists have not been able to explore the potential of these enzymes as anti-infective targets or to develop good approaches to discover new transglycosylase inhibitors. The research proposed here is directed towards obtaining detailed mechanistic and structural information on bacterial transglycosylases, on understanding the mode of inhibition of moenomycin, and on developing strategies to screen transglycosylases for small molecule inhibitors. This work may lead to the development of inhibitors of bacterial transglycosylases that can be used to combat antibiotic resistant microorganisms.
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