title: Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.
abstract: The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Higgins
authors.forename: Ray
authors.initials: R
authors.lastname: Chang
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Debabov
authors.forename: Joey
authors.initials: J
authors.lastname: Leung
authors.forename: Terry
authors.initials: T
authors.lastname: Wu
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Krause
authors.forename: Erik
authors.initials: E
authors.lastname: Sandvik
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Hubbard
authors.forename: Koné
authors.initials: K
authors.lastname: Kaniga
authors.forename: Donald E
authors.initials: DE
authors.lastname: Schmidt
authors.forename: Qiufeng
authors.initials: Q
authors.lastname: Gao
authors.forename: Robert T
authors.initials: RT
authors.lastname: Cass
authors.forename: Dane E
authors.initials: DE
authors.lastname: Karr
authors.forename: Bret M
authors.initials: BM
authors.lastname: Benton
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Humphrey
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D000077427:Lipoglycopeptides; D016106:Methicillin Resistance; D010457:Peptidoglycan / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000617:Aminoglycosides; D000077427:Lipoglycopeptides; D010457:Peptidoglycan; C487637:telavancin
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