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Antimicrobial Agents and Chemotherapy, February 2006, p. 428-438, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.428-438.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Mechanism of Antibiotic Resistance Originating in Vancomycin-Intermediate Staphylococcus aureus

Longzhu Cui,1* Akira Iwamoto,2 Jian-Qi Lian,1,{dagger} Hui-min Neoh,1 Toshiki Maruyama,3 Yataro Horikawa,4 and Keiichi Hiramatsu1

Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421,1 Advanced Science Research Center,3 Japan Atomic Energy Research Institute, Tokai, Ibaraki, 319-1195,2 Department of Physics, Faculty of Medicine, Juntendo University, Inba-gun, Chiba, 270-1695, Japan4

Received 20 June 2005/ Returned for modification 14 August 2005/ Accepted 5 November 2005

As an aggressive pathogen, Staphylococcus aureus poses a significant public health threat and is becoming increasingly resistant to currently available antibiotics, including vancomycin, the drug of last resort for gram-positive bacterial infections. S. aureus with intermediate levels of resistance to vancomycin (vancomycin-intermediate S. aureus [VISA]) was first identified in 1996. The resistance mechanism of VISA, however, has not yet been clarified. We have previously shown that cell wall thickening is a common feature of VISA, and we have proposed that a thickened cell wall is a phenotypic determinant for vancomycin resistance in VISA (L. Cui, X. Ma, K. Sato, et al., J. Clin. Microbiol. 41:5-14, 2003). Here we show the occurrence of an anomalous diffusion of vancomycin through the VISA cell wall, which is caused by clogging of the cell wall with vancomycin itself. A series of experiments demonstrates that the thickened cell wall of VISA could protect ongoing peptidoglycan biosynthesis in the cytoplasmic membrane from vancomycin inhibition, allowing the cells to continue producing nascent cell wall peptidoglycan and thus making the cells resistant to vancomycin. We conclude that the cooperative effect of the clogging and cell wall thickening enables VISA to prevent vancomycin from reaching its true target in the cytoplasmic membrane, exhibiting a new class of antibiotic resistance in gram-positive pathogens.

* Corresponding author. Mailing address: Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Phone: 81-3-5802-1041. Fax: 81-3-5684-7830. E-mail: longzhu{at}med.juntendo.ac.jp.

{dagger} Present address: Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xinshilu-1, Baqiaoqu, Xi'an, 710038, China.

Antimicrobial Agents and Chemotherapy, February 2006, p. 428-438, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.428-438.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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