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Antimicrobial Agents and Chemotherapy, October 2007, p. 3627-3633, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00431-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Fluorescence Ratio Imaging Microscopy Shows Decreased Access of Vancomycin to Cell Wall Synthetic Sites in Vancomycin-Resistant Staphylococcus aureus

Pedro M. Pereira,¹ Sérgio R. Filipe,² Alexander Tomasz,³ and Mariana G. Pinho^1*

Laboratory of Bacterial Cell Biology, Instituto de Tecnologia Química e Biológica da Universidade Nova de Lisboa, Oeiras, Portugal,¹ Laboratory of Bacterial Cell Surfaces and Pathogenesis, Instituto de Tecnologia Química e Biológica da Universidade Nova de Lisboa, Oeiras, Portugal,² Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, New York 10021³

Received 28 March 2007/ Returned for modification 10 June 2007/ Accepted 17 July 2007

A new method of fluorescence ratio imaging microscopy was used to compare the in vivo binding capacity and the access of a fluorescent derivative of vancomycin to the cell wall synthetic sites in isogenic pairs of vancomycin-susceptible and -resistant laboratory mutants and vancomycin-intermediate and -susceptible clinical isolates of Staphylococcus aureus. Live cells of resistant strains were found to bind approximately 1.5 times more antibiotic, but there was no correlation between the increased binding capacity and the MICs of the strains. In both susceptible and resistant bacteria, the subcellular sites of wall synthesis were localized to the division septa, but the rate of diffusion of drug molecules to these sites was reduced in resistant cells. The findings allow a reinterpretation of the mechanism of vancomycin resistance in which the path of vancomycin to its lethal target (lipid II) is considered to be through the division septum and therefore is dependent on the stage of the staphylococcal cell cycle.

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* Corresponding author. Mailing address: Laboratory of Bacterial Cell Biology, Instituto de Tecnologia Química e Biológica, Av. da Republica, 2781-901 Oeiras, Portugal. Phone: 351 21 4469544. Fax: 351 21 4411277. E-mail: mgpinho{at}itqb.unl.pt

Published ahead of print on 23 July 2007.

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Antimicrobial Agents and Chemotherapy, October 2007, p. 3627-3633, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00431-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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