title: The structural basis for induction of VanB resistance.
abstract: Because teicoplanin and vancomycin are the last line of defense for many bacterial infections, the emergence of resistance to glycopeptide antibiotics in enterococci and streptococci has aroused concern. Despite their similarity in terms of structure and mechanism of action, vancomycin induces the expression of genes that leads to bacterial resistance, and teicoplanin does not. We have used a combination of chemical and enzymatic methods to produce sets of vancomycin and teicoplanin analogues that allow us to consider whether the aglycon, the carbohydrate, or other parts of these molecules stimulate VanB resistance. We show that the teicoplanin and vancomycin aglycons are the structural elements that lead to induction of resistance. We think that lipid-containing analogues of vancomycin, like teicoplanin itself, circumvent resistance because the lipid chain changes the periplasmic distribution of the glycopeptide and, therefore, changes the biosynthetic step that it blocks.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Dong
authors.forename: Markus
authors.initials: M
authors.lastname: Oberthür
authors.forename: Heather C
authors.initials: HC
authors.lastname: Losey
authors.forename: John W
authors.initials: JW
authors.lastname: Anderson
authors.forename: Ulrike S
authors.initials: US
authors.lastname: Eggert
authors.forename: Mark W
authors.initials: MW
authors.lastname: Peczuh
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
authors.forename: Daniel
authors.initials: D
authors.lastname: Kahne
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry*; D013293:Enterococcus faecalis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D017334:Teicoplanin / Q000494:pharmacology; D014158:Transcription, Genetic; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C079913:VanB protein, Enterococcus; D017334:Teicoplanin; D014640:Vancomycin