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Infection and Immunity, September 2005, p. 5988-5994, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5988-5994.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Both Corynebacterium diphtheriae DtxR(E175K) and Mycobacterium tuberculosis IdeR(D177K) Are Dominant Positive Repressors of IdeR-Regulated Genes in M. tuberculosis

Yukari C. Manabe,1,2,3* Christine L. Hatem,1 Anup K. Kesavan,1 Justin Durack,1 and John R. Murphy4

Department of Medicine, School of Medicine,1 Departments of Molecular Microbiology and Immunology,2 International Health, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland,3 Section of Biomolecular Medicine, Boston University School of Medicine, Boston, Massachusetts4

Received 4 January 2005/ Returned for modification 11 February 2005/ Accepted 27 April 2005

The diphtheria toxin repressor (DtxR) is an important iron-dependent transcriptional regulator of known virulence genes in Corynebacterium diphtheriae. The mycobacterial iron-dependent repressor (IdeR) is phylogenetically closely related to DtxR, with high amino acid similarity in the DNA binding and metal ion binding site domains. We have previously shown that an iron-insensitive, dominant-positive dtxR(E175K) mutant allele from Corynebacterium diphtheriae can be expressed in Mycobacterium tuberculosis and results in an attenuated phenotype in mice (Y. C. Manabe, B. J. Saviola, L. Sun, J. R. Murphy, and W. R. Bishai, Proc. Natl. Acad. Sci. USA 96:12844-12848, 1999). In this paper, we report the M. tuberculosis IdeR(D177K) strain that has the cognate point mutation. We tested four known and predicted IdeR-regulated gene promoters (mbtI, Rv2123, Rv3402c, and Rv1519) using a promoterless green fluorescent protein (GFP) construct. GFP expression from these promoters was abrogated under low-iron conditions in the presence of both IdeR(D177K) and DtxR(E175K), a result confirmed by reverse transcription-PCR. The IdeR regulon can be constitutively repressed in the presence of an integrated copy of ideR containing this point mutation. These data also suggest that mutant IdeR(D177K) has a mechanism similar to that of DtxR(E175K); iron insensitivity occurs as a result of SH3-like domain binding interactions that stabilize the intermediate form of the repressor after ancillary metal ion binding. This construct can be used to elucidate further the IdeR regulon and its virulence genes and to differentiate these from genes regulated by SirR, which does not have this domain.

* Corresponding author. Mailing address: Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Rm. 108, Baltimore, MD 21231-1004. Phone: (410) 614-6600. Fax: (410) 614-8173. E-mail: ymanabe{at}jhmi.edu.

Editor: J. L. Flynn

Infection and Immunity, September 2005, p. 5988-5994, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5988-5994.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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