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|Title:||Chemo-Enzymatic Synthesis of Glycopeptide Antibiotics|
|Authors:||C Forneris, Clarissa|
|Advisors:||Seyedsayamdost, Mohammad R|
|Publisher:||Princeton, NJ : Princeton University|
|Abstract:||Since its discovery in the 1950s, vancomycin has been an indispensable drug for the treatment of life-threatening bacterial infections. After 60 years of use in the clinic, it remains relevant, as one of the few antibiotic drugs effective against multi-drug resistant pathogens. The discovery of this compound has not only played an essential role in modern medicine, but also launched significant advancements in chemistry and biology. Its discovery founded a novel class of natural products, the glycopeptide antibiotics (GPAs), that now spams hundreds of members with complex chemical structures and powerful bioactivities. Its impressive chemical syntheses fundamentally changed the notions of what synthetic chemistry could achieve. Lastly, the study of vancomycin’s biosynthesis has pushed the limits of our understanding of natural product biosynthesis and uncovered a wide range of novel biological transformations. In spite of vancomycin’s outstanding importance, its use as an antibiotic drug is threatened by the ever-present problem of bacterial resistance. The inevitable emergence of resistance to current drugs among pathogens demands a constant supply of new treatments. Synthetic derivatization of known natural products has proven to be the most successful way to create new and more potent antibiotics. Nonetheless, this approach has been severely restricted within the glycopeptide family of molecules. Now, with the identification of vancomycin-resistant microorganisms, accessing variants of GPAs becomes essential as last-resort drugs are no longer effective. Until recently, the preparation of such vancomycin variants rested on two pillars: semi-synthetic modifications of the isolated drug, or total synthesis. Although important, these approaches incur severe limitations. Herein, we disclose a novel strategy to access vancomycin and its derivatives. This approach combines chemical and biosynthetic methods, resulting in a simple and flexible preparation of GPAs. By recreating the biosynthetic logic in vitro and reconstituting the activities of the native biosynthetic metalloenzymes, we are able to expeditiously synthesize the vancomycin core from a simple precursor. Through the study of reactivity and mechanism of the key P450s, we have broadened the catalytic capabilities of these enzymes, and prepared novel vancomycin analogs. Additionally, our efforts toward chemo-enzymatic synthesis of GPAs have afforded insights into the biosynthesis of vancomycin.|
|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:||Chemistry|
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