Carbohydrate-modified analogs of vancomycin are highly promising leads for overcoming bacterial resistance to this last-line-of-defense antibiotic. Unfortunately, there are few methodologies available to alter natural product carbohydrate ligands. This limitation makes structure-activity relationships difficult to establish and slows the pace of drug discovery. We propose to develop combinatorial biosynthesis methodology to create novel carbohydrate-derivatized natural product analogs, and further diversify these products using chemoselective ligation. Using the described tandem combinatorial biosynthesis/chemoselective ligation approach we will generate libraries of compounds, as well as generate vancomycin/membrane-active antibiotic chimerae. The proposed research will potentially produce new drug leads and elucidate structure activity relationships.
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| Langenhan, Joseph M; Peters, Noel R; Guzei, Ilia A et al. (2005) Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization. Proc Natl Acad Sci U S A 102:12305-10 |
