1. Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds
- Author
-
Yi-Shan Li, Chuen-Jiuan Huang, Gan-Hong Chen, Ming-Daw Tsai, Li-Jen Hsu, Yu-Hou Chen, Tsung-Lin Li, Chia-Cheng Chou, Yu-Chen Liu, Syue-Yi Lyu, Yu-Ting Huang, and Hsiu-Chien Chan
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Teicoplanin ,Protein Conformation ,Drug Resistance, Microbial ,Cell Biology ,Reaction intermediate ,Microbial Sensitivity Tests ,Biology ,Antimicrobial ,Glycopeptide ,Mass Spectrometry ,Multiple drug resistance ,Enzyme ,Protein structure ,chemistry ,Anti-Infective Agents ,Oxidoreductase ,Vancomycin ,medicine ,Enterococcus faecalis ,Molecular Biology ,Oxidation-Reduction ,medicine.drug - 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.
- Published
- 2010