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Antimicrobial Agents and Chemotherapy, August 2009, p. 3375-3383, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01710-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Telavancin Disrupts the Functional Integrity of the Bacterial Membrane through Targeted Interaction with the Cell Wall Precursor Lipid II {triangledown} ,{dagger}

Christopher S. Lunde,* Stephanie R. Hartouni, James W. Janc, Mathai Mammen, Patrick P. Humphrey, and Bret M. Benton

Theravance, Inc., South San Francisco, California 94080

Received 23 December 2008/ Returned for modification 22 February 2009/ Accepted 15 May 2009

Telavancin is an investigational lipoglycopeptide antibiotic currently being developed for the treatment of serious infections caused by gram-positive bacteria. The bactericidal action of telavancin results from a mechanism that combines the inhibition of cell wall synthesis and the disruption of membrane barrier function. The purpose of the present study was to further elucidate the mechanism by which telavancin interacts with the bacterial membrane. A flow cytometry assay with the diethyloxacarbocyanine dye DiOC2(3) was used to probe the membrane potential of actively growing Staphylococcus aureus cultures. Telavancin caused pronounced membrane depolarization that was both time and concentration dependent. Membrane depolarization was demonstrated against a reference S. aureus strain as well as phenotypically diverse isolates expressing clinically important methicillin-resistant (MRSA), vancomycin-intermediate (VISA), and heterogeneous VISA (hVISA) phenotypes. The cell wall precursor lipid II was shown to play an essential role in telavancin-induced depolarization. This was demonstrated both in competition binding experiments with exogenous D-Ala-D-Ala-containing ligand and in experiments with cells expressing altered levels of lipid II. Finally, monitoring of the optical density of S. aureus cultures exposed to telavancin showed that cell lysis does not occur during the time course in which membrane depolarization and bactericidal activity are observed. Taken together, these data indicate that telavancin's membrane mechanism requires interaction with lipid II, a high-affinity target that mediates binding to the bacterial membrane. The targeted interaction with lipid II and the consequent disruption of both peptidoglycan synthesis and membrane barrier function provide a mechanistic basis for the improved antibacterial properties of telavancin relative to those of vancomycin.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080. Phone: (650) 808-3753. Fax: (650) 808-6186. E-mail: clunde{at}theravance.com

{triangledown} Published ahead of print on 26 May 2009.

{dagger} The authors have paid a fee to allow immediate free access to this article.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3375-3383, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01710-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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