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J. Biol. Chem., Vol. 279, Issue 5, 3398-3407, January 30, 2004

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High Level Oxacillin and Vancomycin Resistance and Altered Cell Wall Composition in Staphylococcus aureus Carrying the Staphylococcal mecA and the Enterococcal vanA Gene Complex^*

Anatoly Severin, Keiko Tabei, Fred Tenover¶, Marilyn Chung, Nancy Clarke¶, and Alexander Tomasz||

From the The Rockefeller University, New York, New York 10021, Wyeth Research, Pearl River, New York 10965, and the ^¶Division of Healthcare Quality Promotion (G-08), Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Recently, for the first time in the history of this bacterial species, methicillin-resistant Staphylococcus aureus (MRSA) carrying the enterococcal vanA gene complex and expressing high level resistance to vancomycin was identified in clinical specimens (CDC (2002) MMWR 51, 565–567). The purpose of our studies was to understand how vanA is expressed in the heterologous background of S. aureus and how it interacts with the mecA-based resistance mechanism, which is also present in these strains and is targeted on cell wall biosynthesis. The vanA-containing staphylococcal plasmid was transferred from the clinical vancomycin-resistant S. aureus (VRSA) strain HIP11714(CDC (2002) MMWR 51, 565–567) to the methicillin-resistant S. aureus (MRSA) strain COL for which extensive genetic and biochemical information is available on staphylococcal cell wall biochemistry and drug resistance mechanisms. The transconjugant named COLVA showed high and homogeneous resistance to both oxacillin and vancomycin. COLVA grown in vancomycin-containing medium produced an abnormal peptidoglycan: all pentapeptides were replaced by tetrapeptides, and the peptidoglycan contained at least 22 novel muropeptide species that frequently showed a deficit or complete absence of pentaglycine branches. The UDP-MurNAc-pentapeptide, the major component of the cell wall precursor pool in vancomycin-sensitive cells was replaced by UDP-MurNAc-depsipeptide and UDP-MurNAc-tetrapeptide. Transposon inactivation of the -lactam resistance gene mecA caused complete loss of -lactam resistance but had no effect on the expression of vancomycin resistance. The two major antibiotic resistance mechanisms encoded by mecA and vanA residing in the same S. aureus appear to use different sets of enzymes for the assembly of cell walls.

Received for publication, August 28, 2003 , and in revised form, October 23, 2003.

^* This work was supported by Grant 1-RO1-AI45738 from the United States Public Health Service. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: The Rockefeller University, 1230 York Ave., New York, NY 10021. Tel.: 212-327-8277; Fax: 212-327-8688; E-mail: tomasz{at}mail.rockefeller.edu.

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