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Antimicrobial Agents and Chemotherapy, March 2005, p. 1127-1134, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1127-1134.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Deborah L. Higgins,1 Ray Chang,1 Dmitri V. Debabov,1 Joey Leung,1 Terry Wu,1 Kevin M. Krause,1 Erik Sandvik,1 Jeffrey M. Hubbard,1 Koné Kaniga,1 Donald E. Schmidt Jr.,1 Qiufeng Gao,1 Robert T. Cass,1 Dane E. Karr,1 Bret M. Benton,1* and Patrick P. Humphrey1

Theravance, Inc., South San Francisco, California1

Received 8 July 2004/ Returned for modification 16 August 2004/ Accepted 31 October 2004

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.

* Corresponding author. Mailing address: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080. Phone: (650) 808-6158. Fax: (650) 808-6186. E-mail: bbenton{at}theravance.com.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1127-1134, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1127-1134.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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