Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds
Resource
NATURE CHEMICAL BIOLOGY, 7(5), 304-309
Journal
Nature Chemical Biology
Pages
304-309
Date Issued
2011
Date
2011
Author(s)
Liu, Yu-Chen
Li, Yi-Shan
Lyu, Syue-Yi
Hsu, Li-Jen
Chen, Yu-Hou
Huang, Yu-Ting
Chan, Hsiu-Chien
Huang, Chuen-Jiuan
Chen, Gan-Hong
Chou, Chia-Cheng
Tsai, Ming-Daw
Li, Tsung-Lin
Abstract
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. © 2011 Nature America, Inc. All rights reserved.
Type
journal article
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