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Journal of Bacteriology, September 2000, p. 4889-4898, Vol. 182, No. 17
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival

Todd P. Primm,1 Susan J. Andersen,2 Valerie Mizrahi,2 David Avarbock,3 Harvey Rubin,3,* and Clifton E. Barry III1,*

Tuberculosis Research Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852,1 Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,3 and MRC/SAIMR/WITS Molecular Mycobacteriology Research Unit, South African Institute for Medical Research, and Department of Molecular Medicine and Hematology, University of Witwatersrand Medical School, Johannesburg, South Africa2

Received 11 April 2000/Accepted 16 June 2000

The stringent response utilizes hyperphosphorylated guanine [(p)ppGpp] as a signaling molecule to control bacterial gene expression involved in long-term survival under starvation conditions. In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium tuberculosis contains a single homolog of these proteins (RelMtb) and responds to nutrient starvation by producing (p)ppGpp. A relMtb knockout strain was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The relMtb mutant displayed a significantly slower aerobic growth rate than the wild type in synthetic liquid media, whether rich or minimal. The growth rate of the wild type was equivalent to that of the mutant when citrate or phospholipid was employed as the sole carbon source. These two organisms also showed identical growth rates within a human macrophage-like cell line. These results suggest that the in vivo carbon source does not represent a stressful condition for the bacilli, since it appears to be utilized in a similar RelMtb-independent manner. In vitro growth in liquid media represents a condition that benefits from RelMtb-mediated adaptation. Long-term survival of the relMtb mutant during in vitro starvation or nutrient run out in normal media was significantly impaired compared to that in the wild type. In addition, the mutant was significantly less able to survive extended anerobic incubation than the wild-type virulent organism. Thus, the RelMtb protein is required for long-term survival of pathogenic mycobacteria under starvation conditions.

* Corresponding author. Mailing address for C. E. Barry III: Tuberculosis Research Section, LHD/NIAID, National Institutes of Health, Twinbrook II, Room 239, 12441 Parklawn Dr., Rockville, MD 20852. Phone: (301) 435-7509. Fax: (301) 402-0993. E-mail: clifton_barry{at}nih.gov. Mailing address for H. Rubin: University of Pennsylvania, 225 Johnson Pavilion, Philadelphia, PA 19104. Phone: (215) 662-6475. Fax: (215) 662-7842. E-mail: rubinh{at}mail.med.upenn.edu.

Journal of Bacteriology, September 2000, p. 4889-4898, Vol. 182, No. 17
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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