Tsung-Lin Li - Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds

Document created by Tsung-Lin Li on Aug 22, 2014
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  In the search for new efficacious antibiotics, biosynthetic   engineering offers attractive opportunities to introduce minor   alterations to antibiotic structures that may overcome   resistance. Dbv29, a flavin-containing oxidase, catalyzes the   four-electron oxidation of a vancomycin-like   glycopeptide to yield A40926. Structural and biochemical   examination of Dbv29 now provides insights into residues that   govern flavinylation and activity, protein conformation and   reaction mechanism. In particular, the serendipitous discovery of   a reaction intermediate in the crystal structure led us to   identify an unexpected opportunity to intercept the normal enzyme   mechanism at two different points to create new teicoplanin analogs.   Using this method, we synthesized families of antibiotic analogs   with amidated and aminated lipid chains, some of which showed   marked potency and efficacy against multidrug resistant   pathogens. This method offers a new strategy for the development   of chemical diversity to combat antibacterial resistance.

  Address (URL): http://www.nature.com/nchembio/journal/v7/n5/full/nchembio.556.html