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Antimicrobial Agents and Chemotherapy, January 2005, p. 161-169, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.161-169.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Effect of Promoter Region Mutations and mgrA Overexpression on Transcription of norA, Which Encodes a Staphylococcus aureus Multidrug Efflux Transporter

Glenn W. Kaatz,1,2* Rama V. Thyagarajan,2 and Susan M. Seo2

The John D. Dingell Department of Veteran's Affairs Medical Center,1 the Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan2

Received 1 June 2004/ Returned for modification 25 August 2004/ Accepted 19 September 2004

NorA is a Staphylococcus aureus multidrug transporter that confers resistance to structurally distinct compounds. The MgrA global regulatory protein is reported to augment norA expression when mgrA is overexpressed from an undefined plasmid-based promoter. Further details about norA regulatory mechanisms are scant. A chromosomal norA::lacZ transcriptional fusion was constructed in different S. aureus strains, and allele replacement was used to define the relevance of promoter region sequences to norA expression. The effect of mgrA overexpression in wild-type and mutant backgrounds was also determined. Contrary to existing data, overexpression of mgrA repressed norA transcription in all parent and selected norA promoter mutant strains in a dose-dependent fashion. Disruption of a near-perfect inverted repeat or other putative regulatory protein binding sites did not affect norA transcription, but the repressive effect of mgrA overexpression was blunted in these mutants. This result, and the conservation of all of these motifs in S. aureus, suggests that their presence is required for the full effect of MgrA, or other regulatory proteins, on norA expression. Mutations at the +5 nucleotide of norA mRNA (flqB mutations) had a major impact; all resulted in markedly increased norA expression that was significantly reversed by mgrA overexpression. The flqB position of norA mRNA is part of a conserved imperfect inverted repeat; it is feasible that this motif could be a binding site for a norA regulatory protein.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, B4333 John D. Dingell VA Medical Center, 4646 John R, Detroit, MI 48201. Phone: (313) 576-4487. Fax: (313) 576-1112. E-mail: gkaatz{at}juno.com.

Antimicrobial Agents and Chemotherapy, January 2005, p. 161-169, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.161-169.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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