Directed Evolution of Glycosyltransferases

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DESCRIPTION (provided by applicant): The increasing incidence of antibiotic resistant bacterial infections indicates the need for improved constructs to treat enterococcal infected patients. Modification of existing glycopeptide antibiotics, such as vancomycin and teicoplanin, on and around the sugar substitutents has led to the clinical trials of new treatments, including oritavancin. The long-term goal of this research is to develop an improved understanding of the active-site selectivity of glycosyltransferases so that new, non-native carbohydrate-based constructs may be identified for treatment of drug-resistant infections. The specific question addressed in the context of this research is: "How is the native enzyme active site modified in a mutant glycosyltransferase that is capable of glycosylating a non-native substrate?" This research will develop an existing tool in molecular biology, phage display, for the molecular evolution of mutant glycosyltransferases. We believe that identifying enzymes that can glycosylate new substrates will segue into the generation of catalysts able to compete with chemical synthesis for the rapid and large scale production of glycoconjugates.