title: Specificity of induction of the vanA and vanB operons in vancomycin-resistant enterococci by telavancin.
abstract: Telavancin is a bactericidal, semisynthetic lipoglycopeptide indicated in the United States for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria and is under investigation as a once-daily treatment for nosocomial pneumonia. The related vanA and vanB gene clusters mediate acquired resistance to glycopeptides in enterococci by remodeling the dipeptide termini of peptidoglycan precursors from D-alanyl-D-alanine (D-Ala-D-Ala) to D-alanyl-D-lactate (D-Ala-D-Lac). In this study, we assessed the ability of telavancin to induce the expression of van genes in VanA- and VanB-type strains of vancomycin-resistant enterococci. Vancomycin, teicoplanin, and telavancin efficiently induced VanX activity in VanA-type strains, while VanX activity in VanB-type isolates was inducible by vancomycin but not by teicoplanin or telavancin. In VanA-type strains treated with vancomycin or telavancin, high levels of D-Ala-D-Lac-containing pentadepsipeptide were measured, while D-Ala-D-Ala pentapeptide was present at very low levels or not detected at all. In VanB-type strains, vancomycin but not telavancin induced high levels of pentadepsipeptide, while pentapeptide was not detected. Although vancomycin, teicoplanin, and telavancin induced similar levels of VanX activity in VanA-type strains, these organisms were more sensitive to telavancin, which displayed MIC values that were 32- and 128-fold lower than those of vancomycin and teicoplanin, respectively.
authors.affiliation: Molecular and Cellular Biology Department, Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. chill@theravance.com
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hill
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Krause
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lewis
authors.forename: Johanne
authors.initials: J
authors.lastname: Blais
authors.forename: Bret M
authors.initials: BM
authors.lastname: Benton
authors.forename: Mathai
authors.initials: M
authors.lastname: Mammen
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Humphrey
authors.forename: Alfred
authors.initials: A
authors.lastname: Kinana
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D019729:Carbon-Oxygen Ligases / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D016983:Enterococcus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D000077427:Lipoglycopeptides; D009876:Operon / Q000187:drug effects* / Q000235:genetics; D017334:Teicoplanin / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000187:drug effects / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000077427:Lipoglycopeptides; C071437:VanA ligase, Bacteria; C079913:VanB protein, Enterococcus; D017334:Teicoplanin; D014640:Vancomycin; D019729:Carbon-Oxygen Ligases; C487637:telavancin
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