Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant <i>Staphylococcus aureus</i>
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- Deborah L. Higgins
- Theravance, Inc., South San Francisco, California
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- Ray Chang
- Theravance, Inc., South San Francisco, California
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- Dmitri V. Debabov
- Theravance, Inc., South San Francisco, California
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- Joey Leung
- Theravance, Inc., South San Francisco, California
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- Terry Wu
- Theravance, Inc., South San Francisco, California
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- Kevin M. Krause
- Theravance, Inc., South San Francisco, California
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- Erik Sandvik
- Theravance, Inc., South San Francisco, California
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- Jeffrey M. Hubbard
- Theravance, Inc., South San Francisco, California
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- Koné Kaniga
- Theravance, Inc., South San Francisco, California
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- Donald E. Schmidt
- Theravance, Inc., South San Francisco, California
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- Qiufeng Gao
- Theravance, Inc., South San Francisco, California
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- Robert T. Cass
- Theravance, Inc., South San Francisco, California
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- Dane E. Karr
- Theravance, Inc., South San Francisco, California
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- Bret M. Benton
- Theravance, Inc., South San Francisco, California
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- Patrick P. Humphrey
- Theravance, Inc., South San Francisco, California
抄録
<jats:title>ABSTRACT</jats:title> <jats:p> 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 <jats:italic>N</jats:italic> , <jats:italic>N</jats:italic> ′-diacetyl- <jats:sc>l</jats:sc> -lysinyl- <jats:sc>d</jats:sc> -alanyl- <jats:sc>d</jats:sc> -alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant <jats:italic>Staphylococcus aureus</jats:italic> , telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K <jats:sup>+</jats:sup> . 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. </jats:p>
収録刊行物
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- Antimicrobial Agents and Chemotherapy
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Antimicrobial Agents and Chemotherapy 49 (3), 1127-1134, 2005-03
American Society for Microbiology
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詳細情報 詳細情報について
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- CRID
- 1363107368356108288
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- NII論文ID
- 30020633462
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- ISSN
- 10986596
- 00664804
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