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Antimicrobial Agents and Chemotherapy, April 2007, p. 1274-1280, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01060-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Lack of Relationship between Purine Biosynthesis and Vancomycin Resistance in Staphylococcus aureus: a Cautionary Tale for Microarray Interpretation{triangledown}

Paige M. Fox,1 Michael W. Climo,2,3 and Gordon L. Archer1,2*

Departments of Microbiology and Immunology,1 Medicine, Virginia Commonwealth University School of Medicine,2 Hunter Holmes McGuire Veteran Affairs Medical Center, Richmond, Virginia3

Received 22 August 2006/ Returned for modification 27 October 2006/ Accepted 4 January 2007

Previous microarray data (E. Mongodin, J. Finan, M. W. Climo, A. Rosato, S. Gill, and G. L. Archer, J. Bacteriol. 185:4638-4643, 2003) noted an association in two vancomycin-intermediate Staphylococcus aureus (VISA) strains between high-level, passage-induced vancomycin resistance, a marked increase in the transcription of purine biosynthetic genes, and mutation of the putative purine regulator purR. Initial studies to report on the possible association between vancomycin resistance and alterations in purine metabolism in one of these strains (VP-32) confirmed, by Western analysis, an increase in the translation of PurH and PurM, two purine pathway enzymes. In addition, PurR was identified, by knockout and complementation in a vancomycin-susceptible strain, as a repressor of the purine biosynthetic operon in S. aureus, and the PurR missense mutation was shown to inactivate the repressor. However, despite the apparent relationship between increased purine biosynthesis and increased vancomycin resistance in VP-32, neither the addition of exogenous purines to a defined growth medium nor the truncation or inactivation of purR improved the growth of vancomycin-susceptible S. aureus in the presence of vancomycin. Furthermore, the passage of additional vancomycin-susceptible and VISA strains to high-level vancomycin resistance occurred without changes in cellular purine metabolism or mutation of purR despite the development of thickened cell walls in passaged strains. Thus, we could confirm neither a role for altered purine metabolism in the development of vancomycin resistance nor its requirement for the maintenance of a thickened cell wall. The failure of biochemical and physiological studies to support the association between transcription and phenotype initially found in careful microarray studies emphasizes the importance of follow-up investigations to confirm microarray observations.

* Corresponding author. Mailing address: Virginia Commonwealth University, P.O. Box 980565, 1101 East Marshall Street, Richmond, VA 23298. Phone: (804) 828-0678. Fax: (804) 828-5022. E-mail: garcher{at}vcu.edu

{triangledown} Published ahead of print on 22 January 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1274-1280, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01060-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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