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Antimicrobial Agents and Chemotherapy, May 2002, p. 1492-1502, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1492-1502.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Accessory Gene Regulator (agr) Locus in Geographically Diverse Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin

George Sakoulas,1,2* George M. Eliopoulos,1,2 Robert C. Moellering, Jr.,1,2 Christine Wennersten,1 Lata Venkataraman,3 Richard P. Novick,4 and Howard S. Gold1,2

Department of Medicine,1 Division of Laboratory and Transfusion Medicine, Department of Pathology, Beth Israel Deaconess Medical Center,3 Harvard Medical School, Boston, Massachusetts 02115,2 Skirball Institute of Biomolecular Medicine and New York University School of Medicine, New York, New York 100164

Received 10 July 2001/ Returned for modification 12 November 2001/ Accepted 20 January 2002

The majority of infections with glycopeptide intermediate-level resistant Staphylococcus aureus (GISA) originate in biomedical devices, suggesting a possible increased ability of these strains to produce biofilm. Loss of function of the accessory gene regulator (agr) of S. aureus has been suggested to confer an enhanced ability to bind to polystyrene. We studied agr in GISA, hetero-GISA, and related glycopeptide-susceptible S. aureus isolates. All GISA strains from diverse geographic origins belong to agr group II. All GISA strains were defective in agr function, as demonstrated by their inability to produce delta-hemolysin. Hetero-GISA isolate A5940 demonstrated a nonsense mutation in agrA that was not present in a pulsed-field gel electrophoresis-indistinguishable vancomycin-susceptible isolate from the same patient. Various other agr point mutations were noted in several clinical GISA and hetero-GISA isolates. A laboratory-generated agr-null strain demonstrated a small but reproducible increase in vancomycin heteroresistance after growth in vitro in subinhibitory concentrations of vancomycin. This was not seen in the isogenic agr group II parent strain in which agr was intact. The in vitro bactericidal activity of vancomycin was attenuated in the agr-null strain compared to the parent strain. These findings imply that compromised agr function is advantageous to clinical isolates of S. aureus toward the development of vancomycin heteroresistance, perhaps through the development of vancomycin tolerance.

* Corresponding author. Mailing address: Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Kennedy Bldg., 6th Floor, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 632-0760. Fax: (617) 632-0766. E-mail: gsakoula{at}caregroup.harvard.edu.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1492-1502, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1492-1502.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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