title: Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds.
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.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Liu
authors.forename: Yi-Shan
authors.initials: YS
authors.lastname: Li
authors.forename: Syue-Yi
authors.initials: SY
authors.lastname: Lyu
authors.forename: Li-Jen
authors.initials: LJ
authors.lastname: Hsu
authors.forename: Yu-Hou
authors.initials: YH
authors.lastname: Chen
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.forename: Hsiu-Chien
authors.initials: HC
authors.lastname: Chan
authors.forename: Chuen-Jiuan
authors.initials: CJ
authors.lastname: Huang
authors.forename: Gan-Hong
authors.initials: GH
authors.lastname: Chen
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Chou
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Li
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D013293:Enterococcus faecalis / Q000145:classification / Q000187:drug effects*; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction; D011487:Protein Conformation; D017334:Teicoplanin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014640:Vancomycin / Q000737:chemistry / Q000494:pharmacology
chemical_list: C054981:A 40926; D000890:Anti-Infective Agents; D017334:Teicoplanin; D014640:Vancomycin