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Antimicrobial Agents and Chemotherapy, November 2001, p. 3070-3075, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3070-3075.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role of Penicillin-Binding Protein 4 in Expression of Vancomycin Resistance among Clinical Isolates of Oxacillin-Resistant Staphylococcus aureus

J. E. Finan,1 Gordon L. Archer,1,2 Michael J. Pucci,3 and Michael W. Climo1,4,*

Departments of Medicine1 and Microbiology/Immunology,2 Medical College of Virginia at Virginia Commonwealth University, and Hunter Holmes McGuire Veterans Affairs Medical Center,4 Richmond, Virginia, and The Bristol-Meyers Squibb Pharmaceutical Institute, Wallingford, Connecticut3

Received 30 January 2001/Returned for modification 30 April 2001/Accepted 23 July 2001

It has been reported that penicillin-binding protein 4 (PBP4) activity decreases when a vancomycin-susceptible Staphylococcus aureus isolate is passaged in vitro to vancomycin resistance. We analyzed the PBP profiles of four vancomycin intermediately susceptible S. aureus (VISA) clinical isolates and found that PBP4 was undetectable in three isolates (HIP 5827, HIP 5836, and HIP 6297) and markedly reduced in a fourth (Mu50). PBP4 was readily visible in five vancomycin-susceptible, oxacillin-resistant S. aureus (ORSA) isolates. The nucleotide sequences of the pbp4 structural gene and flanking sequences did not different between the VISA and vancomycin-susceptible isolates. Overproduction of PBP4 on a high-copy-number plasmid in the VISA isolates produced a two- to threefold decrease in vancomycin MICs. Inactivation of pbp4 by allelic replacement mutagenesis in three vancomycin-susceptible ORSA strains (COL, RN450M, and N315) led to a decrease in vancomycin susceptibility, an increase in highly vancomycin-resistant subpopulations, and decreased cell wall cross-linking by high-performance liquid chromatography analysis. Complementation of the COL mutant with plasmid-encoded pbp4 restored the vancomycin MIC and increased cell wall cross-linking. These data suggest that alterations in PBP4 expression are at least partially responsible for the VISA phenotype.

* Corresponding author. Mailing address: Hunter Holmes McGuire Veterans Affairs Medical Center, 1201 Broad Rock Blvd., Section 111-C, Richmond, VA 23249. Phone: (804) 675-5018. Fax: (804) 675-5437. E-mail: michael.climo{at}med.va.gov.

Antimicrobial Agents and Chemotherapy, November 2001, p. 3070-3075, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3070-3075.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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