Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus

Longzhu Cui, Akira Iwamoto, Jian Qi Lian, Hui Min Neoh, Toshiki Maruyama, Yataro Horikawa, Keiichi Hiramatsu

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)428-438
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 2006
Externally publishedYes

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Vancomycin
Microbial Drug Resistance
Staphylococcus aureus
Cell Wall
Vancomycin Resistance
Peptidoglycan
Gram-Positive Bacterial Infections
Cell Membrane
Public Health
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. / Cui, Longzhu; Iwamoto, Akira; Lian, Jian Qi; Neoh, Hui Min; Maruyama, Toshiki; Horikawa, Yataro; Hiramatsu, Keiichi.

In: Antimicrobial Agents and Chemotherapy, Vol. 50, No. 2, 02.2006, p. 428-438.

Research output: Contribution to journalArticle

Cui, Longzhu ; Iwamoto, Akira ; Lian, Jian Qi ; Neoh, Hui Min ; Maruyama, Toshiki ; Horikawa, Yataro ; Hiramatsu, Keiichi. / Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. In: Antimicrobial Agents and Chemotherapy. 2006 ; Vol. 50, No. 2. pp. 428-438.
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